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Poudineh M, Mohammadyari F, Parsamanesh N, Jamialahmadi T, Kesharwani P, Sahebkar A. Cell and gene therapeutic approaches in non-alcoholic fatty liver disease. Gene 2025; 956:149466. [PMID: 40189164 DOI: 10.1016/j.gene.2025.149466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Revised: 03/14/2025] [Accepted: 03/31/2025] [Indexed: 04/11/2025]
Abstract
Non-Alcoholic Fatty Liver Disease (NAFLD) refers to a range of conditions marked by the buildup of triglycerides in liver cells, accompanied by inflammation, which contributes to liver damage, clinical symptoms, and histopathological alterations. Multiple molecular pathways contribute to NAFLD pathogenesis, including immune dysregulation, endoplasmic reticulum stress, and tissue injury. Both the innate and adaptive immune systems play crucial roles in disease progression, with intricate crosstalk between liver and immune cells driving NAFLD development. Among emerging therapeutic strategies, cell and gene-based therapies have shown promise. This study reviews the pathophysiological mechanisms of NAFLD and explores the therapeutic potential of cell-based interventions, highlighting their immunomodulatory effects, inhibition of hepatic stellate cells, promotion of hepatocyte regeneration, and potential for hepatocyte differentiation. Additionally, we examine gene delivery vectors designed to target NAFLD, focusing on their role in engineering hepatocytes through gene addition or editing to enhance therapeutic efficacy.
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Affiliation(s)
| | | | - Negin Parsamanesh
- Metabolic Diseases Research Center, Zanjan University of Medical Sciences, Zanjan, Iran; Department of Genetics and Molecular Medicine, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Tananz Jamialahmadi
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Medical Toxicology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Prashant Kesharwani
- Department of Pharmaceutical Sciences, Dr. Harisingh Gour Vishwavidyalaya, Sagar, Madhya Pradesh 470003, India.
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Centre for Research Impact and Outcome, Chitkara University, Rajpura 140417, Punjab, India; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Qian Y, Liu C, Zeng X, Li LC. RNAa: Mechanisms, therapeutic potential, and clinical progress. MOLECULAR THERAPY. NUCLEIC ACIDS 2025; 36:102494. [PMID: 40125270 PMCID: PMC11930103 DOI: 10.1016/j.omtn.2025.102494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 03/25/2025]
Abstract
RNA activation (RNAa), a gene regulatory mechanism mediated by small activating RNAs (saRNAs) and microRNAs (miRNAs), has significant implications for therapeutic applications. Unlike small interfering RNA (siRNA), which is known for gene silencing in RNA interference (RNAi), synthetic saRNAs can stably upregulate target gene expression at the transcriptional level through the assembly of the RNA-induced transcriptional activation (RITA) complex. Moreover, the dual functionality of endogenous miRNAs in RNAa (hereafter referred to as mi-RNAa) reveals their complex role in cellular processes and disease pathology. Emerging studies suggest saRNAs' potential as a novel therapeutic modality for diseases such as metabolic disorders, hearing loss, tumors, and Alzheimer's. Notably, MTL-CEBPA, the first saRNA drug candidate, shows promise in hepatocellular carcinoma treatment, while RAG-01 is being explored for non-muscle-invasive bladder cancer, highlighting clinical advancements in RNAa. This review synthesizes our current understanding of the mechanisms of RNAa and highlights recent advancements in the study of mi-RNAa and the therapeutic development of saRNAs.
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Affiliation(s)
- Yukang Qian
- Institute of Reproductive Medicine, School of Medicine, Nantong University, Nantong, Jiangsu 226019, China
| | - Cody Liu
- Univeristy of California, Davis, Davis, CA 95616, USA
| | - Xuhui Zeng
- Institute of Reproductive Medicine, School of Medicine, Nantong University, Nantong, Jiangsu 226019, China
| | - Long-Cheng Li
- Institute of Reproductive Medicine, School of Medicine, Nantong University, Nantong, Jiangsu 226019, China
- Ractigen Therapeutics, Nantong, Jiangsu 226400, China
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Liu M, Wang Y, Zhang Y, Hu D, Tang L, Zhou B, Yang L. Landscape of small nucleic acid therapeutics: moving from the bench to the clinic as next-generation medicines. Signal Transduct Target Ther 2025; 10:73. [PMID: 40059188 PMCID: PMC11891339 DOI: 10.1038/s41392-024-02112-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 10/23/2024] [Accepted: 12/13/2024] [Indexed: 03/17/2025] Open
Abstract
The ability of small nucleic acids to modulate gene expression via a range of processes has been widely explored. Compared with conventional treatments, small nucleic acid therapeutics have the potential to achieve long-lasting or even curative effects via gene editing. As a result of recent technological advances, efficient small nucleic acid delivery for therapeutic and biomedical applications has been achieved, accelerating their clinical translation. Here, we review the increasing number of small nucleic acid therapeutic classes and the most common chemical modifications and delivery platforms. We also discuss the key advances in the design, development and therapeutic application of each delivery platform. Furthermore, this review presents comprehensive profiles of currently approved small nucleic acid drugs, including 11 antisense oligonucleotides (ASOs), 2 aptamers and 6 siRNA drugs, summarizing their modifications, disease-specific mechanisms of action and delivery strategies. Other candidates whose clinical trial status has been recorded and updated are also discussed. We also consider strategic issues such as important safety considerations, novel vectors and hurdles for translating academic breakthroughs to the clinic. Small nucleic acid therapeutics have produced favorable results in clinical trials and have the potential to address previously "undruggable" targets, suggesting that they could be useful for guiding the development of additional clinical candidates.
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Affiliation(s)
- Mohan Liu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yusi Wang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yibing Zhang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Die Hu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Lin Tang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Bailing Zhou
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Li Yang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
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Soubeyrand S, Lau P, McPherson R. Distinct roles of Constitutive Photomorphogenesis Protein 1 homolog (COP1) in human hepatocyte models. Front Mol Biosci 2025; 12:1548582. [PMID: 39990870 PMCID: PMC11842253 DOI: 10.3389/fmolb.2025.1548582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Accepted: 01/21/2025] [Indexed: 02/25/2025] Open
Abstract
Introduction Constitutive Photomorphogenesis Protein 1 homolog (COP1) is a conserved E3 ligase with key roles in several biological systems. Prior work in hepatocyte-derived tumors categorized COP1 as an oncogene, but its role in untransformed hepatocytes remains largely unexplored. Here, we have investigated the role of COP1 in primary human hepatocytes and two transformed hepatocyte models, HepG2 and HuH-7 cells. Methods The role of COP1 was tested by silencing and transduction experiments in HepG2, HuH-7, and primary human hepatocytes. Transcription array data of COP1-suppressed cells were generated and analyzed using clustering analyses. Cellular impacts were examined by proliferation assays, qRT-PCR, western blotting, reporter assays, and APOB enzyme-linked immunosorbent assays. Results and Discussion COP1 suppression had no noticeable impact on HepG2 and HuH-7 proliferation and was associated with contrasting rather than congruent transcriptome changes. Transcriptomic changes were consistent with perturbed metabolism in primary hepatocytes and HepG2 cells and impaired cell cycle regulation in HuH-7 cells. In HepG2 and primary hepatocytes but not in HuH-7 cells, COP1 suppression reduced the expression of important hepatic regulators and markers. COP1 downregulation reduced hepatic nuclear factor-4 alpha (HNF4A) abundance and function, as assessed by a lower abundance of key HNF4A targets, reduced APOB secretion, and reporter assays. HNF4A function could be restored by introducing a siRNA-resistant COP1 transgene, whereas HNF4A restoration partially rescued COP1 silencing in HepG2 cells. Our results identify and detail a pivotal regulatory role of COP1 in hepatocytes, in part through HNF4A.
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Affiliation(s)
| | - Paulina Lau
- Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, Canada
| | - Ruth McPherson
- Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, Canada
- Department of Medicine, Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, Canada
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Sethi SC, Singh R, Sahay O, Barik GK, Kalita B. Unveiling the hidden gem: A review of long non-coding RNA NBAT-1 as an emerging tumor suppressor and prognostic biomarker in cancer. Cell Signal 2025; 126:111525. [PMID: 39592019 DOI: 10.1016/j.cellsig.2024.111525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 11/09/2024] [Accepted: 11/20/2024] [Indexed: 11/28/2024]
Abstract
Previously considered junk or non-functional, long non-coding RNAs (lncRNAs) have emerged over the past few decades as pivotal components in both physiological and pathological processes, including cancer. Neuroblastoma-associated transcript-1 (NBAT-1) was initially discovered a decade ago as a risk-associated tumor suppressor lncRNA in neuroblastoma (NB). Subsequent studies have consistently demonstrated that NBAT-1 serves as a dedicated tumor suppressor in many cancers. NBAT-1 is significantly downregulated in cancer, which is closely linked to higher histological grades, increased metastasis, and poor survival in cancer patients suggesting NBAT-1's potential as a prognostic biomarker. In this review, we delve into the current body of literature, elucidating the tumor-suppressive roles of NBAT-1 and the underlying regulatory mechanisms in the context of human malignancies. Additionally, we shed light on the mechanisms contributing to the diminished expression of NBAT-1 and its potential as both a prognostic biomarker and a promising therapeutic target in cancer.
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Affiliation(s)
- Subhash Chandra Sethi
- Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Ragini Singh
- Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Osheen Sahay
- Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Ganesh Kumar Barik
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
| | - Bhargab Kalita
- Amrita Research Center, Amrita Vishwa Vidyapeetham, Amrita Hospital, Mata Amritanandamayi Marg, Faridabad 121002, India.
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Yuan Y, Sun W, Xie J, Zhang Z, Luo J, Han X, Xiong Y, Yang Y, Zhang Y. RNA nanotherapeutics for hepatocellular carcinoma treatment. Theranostics 2025; 15:965-992. [PMID: 39776807 PMCID: PMC11700867 DOI: 10.7150/thno.102964] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 11/22/2024] [Indexed: 01/11/2025] Open
Abstract
Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, particularly due to the limited effectiveness of current therapeutic options for advanced-stage disease. The efficacy of traditional treatments is often compromised by the intricate liver microenvironment and the inherent heterogeneity. RNA-based therapeutics offer a promising alternative, utilizing the innovative approach of targeting aberrant molecular pathways and modulating the tumor microenvironment. The integration of nanotechnology in this field, through the development of advanced nanocarrier delivery systems, especially lipid nanoparticles (LNPs), polymer nanoparticles (PNPs), and bioinspired vectors, enhances the precision and efficacy of RNA therapies. This review highlights the significant progress in RNA nanotherapeutics for HCC treatment, covering micro RNA (miRNA), small interfering RNA (siRNA), message RNA (mRNA), and small activating RNA (saRNA) mediated gene silencing, therapeutic protein restoration, gene activation, cancer vaccines, and concurrent therapy. It further comprehensively discusses the prevailing challenges within this therapeutic landscape and provides a forward-looking perspective on the potential of RNA nanotherapeutics to transform HCC treatment.
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Affiliation(s)
- Yihang Yuan
- The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University and Clinical Cancer Institute of Nanjing University, Nanjing 210008, China
- Department of General Surgery Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School Nanjing University, Nanjing 210008, China
| | - Weijie Sun
- Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233004, China
| | - Jiaqi Xie
- The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University and Clinical Cancer Institute of Nanjing University, Nanjing 210008, China
| | - Ziheng Zhang
- School of Life Sciences, Jiangsu University, Zhenjiang 212013, China
| | - Jing Luo
- Department of Urology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Xiangfei Han
- Center for Nanomedicine and Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Yongfu Xiong
- Department of Hepatobiliary Surgery, Academician (Expert) Workstation, Affiliated Hospital of North Sichuan Medical College, Nanchong 637600, China
| | - Yang Yang
- The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University and Clinical Cancer Institute of Nanjing University, Nanjing 210008, China
| | - Yang Zhang
- Center for Nanomedicine and Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
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Lou W, Zhang L, Wang J. Current status of nucleic acid therapy and its new progress in cancer treatment. Int Immunopharmacol 2024; 142:113157. [PMID: 39288629 DOI: 10.1016/j.intimp.2024.113157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 07/05/2024] [Accepted: 09/09/2024] [Indexed: 09/19/2024]
Abstract
Nucleic acid is an essential biopolymer in all living cells, performing the functions of storing and transmitting genetic information and synthesizing protein. In recent decades, with the progress of science and biotechnology and the continuous exploration of the functions performed by nucleic acid, more and more studies have confirmed that nucleic acid therapy for living organisms has great medical therapeutic potential. Nucleic acid drugs began to become independent therapeutic agents. As a new therapeutic method, nucleic acid therapy plays an important role in the treatment of genetic diseases, viral infections and cancers. There are currently 19 nucleic acid drugs approved by the Food and Drug Administration (FDA). In the following review, we start from principles and advantages of nucleic acid therapy, and briefly describe development history of nucleic acid drugs. And then we give examples of various RNA therapeutic drugs, including antisense oligonucleotides (ASO), mRNA vaccines, small interfering RNA (siRNA) and microRNA (miRNA), aptamers, and small activating RNA (saRNA). In addition, we also focused on the current status of nucleic acid drugs used in cancer therapy and the breakthrough in recent years. Clinical trials of nucleic acid drugs for cancer treatment are under way, conventional radiotherapy and chemotherapy combined with the immunotherapies such as checkpoint inhibitors and nucleic acid drugs may be the main prospects for successful cancer treatment.
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Affiliation(s)
- Wenting Lou
- Department of Surgery, The Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu 322000, China
| | - Leqi Zhang
- Department of Surgery, The Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu 322000, China
| | - Jianwei Wang
- Department of Surgery, The Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu 322000, China; Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, 2nd Affiliated Hospital, Zhejiang University School of Medicine, Jiefang Road 88th, Hangzhou 310009, China.
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Sun X, Setrerrahmane S, Li C, Hu J, Xu H. Nucleic acid drugs: recent progress and future perspectives. Signal Transduct Target Ther 2024; 9:316. [PMID: 39609384 PMCID: PMC11604671 DOI: 10.1038/s41392-024-02035-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 09/20/2024] [Accepted: 10/25/2024] [Indexed: 11/30/2024] Open
Abstract
High efficacy, selectivity and cellular targeting of therapeutic agents has been an active area of investigation for decades. Currently, most clinically approved therapeutics are small molecules or protein/antibody biologics. Targeted action of small molecule drugs remains a challenge in medicine. In addition, many diseases are considered 'undruggable' using standard biomacromolecules. Many of these challenges however, can be addressed using nucleic therapeutics. Nucleic acid drugs (NADs) are a new generation of gene-editing modalities characterized by their high efficiency and rapid development, which have become an active research topic in new drug development field. However, many factors, including their low stability, short half-life, high immunogenicity, tissue targeting, cellular uptake, and endosomal escape, hamper the delivery and clinical application of NADs. Scientists have used chemical modification techniques to improve the physicochemical properties of NADs. In contrast, modified NADs typically require carriers to enter target cells and reach specific intracellular locations. Multiple delivery approaches have been developed to effectively improve intracellular delivery and the in vivo bioavailability of NADs. Several NADs have entered the clinical trial recently, and some have been approved for therapeutic use in different fields. This review summarizes NADs development and evolution and introduces NADs classifications and general delivery strategies, highlighting their success in clinical applications. Additionally, this review discusses the limitations and potential future applications of NADs as gene therapy candidates.
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Affiliation(s)
- Xiaoyi Sun
- Jiangsu Province Engineering Research Center of Synthetic Peptide Drug Discovery and Evaluation, China Pharmaceutical University, Nanjing, 210009, China
| | | | - Chencheng Li
- Jiangsu Province Engineering Research Center of Synthetic Peptide Drug Discovery and Evaluation, China Pharmaceutical University, Nanjing, 210009, China
| | - Jialiang Hu
- Jiangsu Province Engineering Research Center of Synthetic Peptide Drug Discovery and Evaluation, China Pharmaceutical University, Nanjing, 210009, China
| | - Hanmei Xu
- Jiangsu Province Engineering Research Center of Synthetic Peptide Drug Discovery and Evaluation, China Pharmaceutical University, Nanjing, 210009, China.
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Xia Z, Wei Z, Li X, Liu Y, Gu X, Tong J, Huang S, Zhang X, Wang W. C/EBPα-mediated ACSL4-dependent ferroptosis exacerbates tubular injury in diabetic kidney disease. Cell Death Discov 2024; 10:448. [PMID: 39443466 PMCID: PMC11499655 DOI: 10.1038/s41420-024-02179-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 08/05/2024] [Accepted: 09/12/2024] [Indexed: 10/25/2024] Open
Abstract
Diabetic kidney disease (DKD) is a prevalent and debilitating complication of diabetes characterized by progressive renal function decline and a lack of effective treatment options. Here, we investigated the role of the transcription factor CCAAT/enhancer binding protein alpha (C/EBPα) in DKD pathogenesis. Analysis of renal biopsy samples revealed increased C/EBPα expression in patients with DKD. Using RNA sequencing and proteomics, we explored the mechanisms through which the C/EBPα contributes to DKD. Our findings demonstrated that C/EBPα exacerbated tubular injury by promoting acyl-CoA synthetase long-chain family member 4 (ACSL4)-dependent ferroptosis. We identified that C/EBPα upregulated ACSL4 expression by binding to its transcription regulatory sequence (TRS), leading to elevated lipid peroxidation and ferroptosis. Furthermore, inhibition or genetic ablation of C/EBPα attenuated ferroptosis and mitigated tubular injury in DKD. These results highlighted the C/EBPα-ACSL4-ferroptosis pathway as a promising therapeutic target for DKD treatment.
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Affiliation(s)
- Ziru Xia
- Department of Nephrology, Institute of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China
- Institute of Nephrology, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
- Department of General Internal Medicine, West China Second University Hospital, Sichuan University, Chengdu, 610041, China
| | - Zhaonan Wei
- Department of Nephrology, Institute of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China
- Institute of Nephrology, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Xin Li
- Department of Nephrology, Institute of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China
- Institute of Nephrology, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Yunzi Liu
- Department of Nephrology, Institute of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China
- Institute of Nephrology, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Xiangchen Gu
- Department of Nephrology, Institute of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China
- Institute of Nephrology, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
- Department of Nephrology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, People's Republic of China
| | - Jianhua Tong
- Faculty of Medical Laboratory Science, Central Laboratory, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China
| | - Siyi Huang
- Department of Nephrology, Institute of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China
- Institute of Nephrology, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Xiaoyue Zhang
- Department of Nephrology, Institute of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China
- Institute of Nephrology, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Weiming Wang
- Department of Nephrology, Institute of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China.
- Institute of Nephrology, Shanghai Jiao Tong University, School of Medicine, Shanghai, China.
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Pan X, Wang L, Yang J, Li Y, Xu M, Liang C, Liu L, Li Z, Xia C, Pang J, Wang M, Li M, Guo S, Yan P, Ding C, Rosas IO, Yu G. TRβ activation confers AT2-to-AT1 cell differentiation and anti-fibrosis during lung repair via KLF2 and CEBPA. Nat Commun 2024; 15:8672. [PMID: 39375377 PMCID: PMC11458772 DOI: 10.1038/s41467-024-52827-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Accepted: 09/23/2024] [Indexed: 10/09/2024] Open
Abstract
Aberrant repair underlies the pathogenesis of pulmonary fibrosis while effective strategies to convert fibrosis to normal regeneration are scarce. Here, we found that thyroid hormone is decreased in multiple models of lung injury but is essential for lung regeneration. Moreover, thyroid hormone receptor α (TRα) promotes cell proliferation, while TRβ fuels cell maturation in lung regeneration. Using a specific TRβ agonist, sobetirome, we demonstrate that the anti-fibrotic effects of thyroid hormone mainly rely on TRβ in mice. Cellularly, TRβ activation enhances alveolar type-2 (AT2) cell differentiation into AT1 cell and constrains AT2 cell hyperplasia. Molecularly, TRβ activation directly regulates the expression of KLF2 and CEBPA, both of which further synergistically drive the differentiation program of AT1 cells and benefit regeneration and anti-fibrosis. Our findings elucidate the modulation function of the TRβ-KLF2/CEBPA axis on AT2 cell fate and provide a potential treatment strategy to facilitate lung regeneration and anti-fibrosis.
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Affiliation(s)
- Xin Pan
- Pingyuan Laboratory, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Organ Fibrosis, State Key Laboratory of Cell Differentiation and Regulation, College of Life Science, Henan Normal University, Xinxiang, China
| | - Lan Wang
- Pingyuan Laboratory, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Organ Fibrosis, State Key Laboratory of Cell Differentiation and Regulation, College of Life Science, Henan Normal University, Xinxiang, China.
| | - Juntang Yang
- Pingyuan Laboratory, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Organ Fibrosis, State Key Laboratory of Cell Differentiation and Regulation, College of Life Science, Henan Normal University, Xinxiang, China
| | - Yingge Li
- Pingyuan Laboratory, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Organ Fibrosis, State Key Laboratory of Cell Differentiation and Regulation, College of Life Science, Henan Normal University, Xinxiang, China
| | - Min Xu
- Pingyuan Laboratory, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Organ Fibrosis, State Key Laboratory of Cell Differentiation and Regulation, College of Life Science, Henan Normal University, Xinxiang, China
| | - Chenxi Liang
- Pingyuan Laboratory, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Organ Fibrosis, State Key Laboratory of Cell Differentiation and Regulation, College of Life Science, Henan Normal University, Xinxiang, China
| | - Lulu Liu
- Pingyuan Laboratory, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Organ Fibrosis, State Key Laboratory of Cell Differentiation and Regulation, College of Life Science, Henan Normal University, Xinxiang, China
| | - Zhongzheng Li
- Pingyuan Laboratory, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Organ Fibrosis, State Key Laboratory of Cell Differentiation and Regulation, College of Life Science, Henan Normal University, Xinxiang, China
| | - Cong Xia
- Pingyuan Laboratory, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Organ Fibrosis, State Key Laboratory of Cell Differentiation and Regulation, College of Life Science, Henan Normal University, Xinxiang, China
| | - Jiaojiao Pang
- Pingyuan Laboratory, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Organ Fibrosis, State Key Laboratory of Cell Differentiation and Regulation, College of Life Science, Henan Normal University, Xinxiang, China
| | - Mengyuan Wang
- Pingyuan Laboratory, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Organ Fibrosis, State Key Laboratory of Cell Differentiation and Regulation, College of Life Science, Henan Normal University, Xinxiang, China
| | - Meng Li
- Pingyuan Laboratory, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Organ Fibrosis, State Key Laboratory of Cell Differentiation and Regulation, College of Life Science, Henan Normal University, Xinxiang, China
| | - Saiya Guo
- Pingyuan Laboratory, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Organ Fibrosis, State Key Laboratory of Cell Differentiation and Regulation, College of Life Science, Henan Normal University, Xinxiang, China
| | - Peishuo Yan
- Pingyuan Laboratory, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Organ Fibrosis, State Key Laboratory of Cell Differentiation and Regulation, College of Life Science, Henan Normal University, Xinxiang, China
| | - Chen Ding
- State Key Laboratory of Genetic Engineering, Human Phenome Institute, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ivan O Rosas
- Division of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Guoying Yu
- Pingyuan Laboratory, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Organ Fibrosis, State Key Laboratory of Cell Differentiation and Regulation, College of Life Science, Henan Normal University, Xinxiang, China.
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11
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Ming Y, Gong Y, Fu X, Ouyang X, Peng Y, Pu W. Small-molecule-based targeted therapy in liver cancer. Mol Ther 2024; 32:3260-3287. [PMID: 39113358 PMCID: PMC11489561 DOI: 10.1016/j.ymthe.2024.08.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 03/13/2024] [Accepted: 08/02/2024] [Indexed: 08/23/2024] Open
Abstract
Liver cancer is one of the most prevalent malignant tumors worldwide. According to the Barcelona Clinic Liver Cancer staging criteria, clinical guidelines provide tutorials to clinical management of liver cancer at their individual stages. However, most patients diagnosed with liver cancer are at advanced stage; therefore, many researchers conduct investigations on targeted therapy, aiming to improve the overall survival of these patients. To date, small-molecule-based targeted therapies are highly recommended (first line: sorafenib and lenvatinib; second line: regorafenib and cabozantinib) by current the clinical guidelines of the American Society of Clinical Oncology, European Society for Medical Oncology, and National Comprehensive Cancer Network. Herein, we summarize the small-molecule-based targeted therapies in liver cancer, including the approved and preclinical therapies as well as the therapies under clinical trials, and introduce their history of discovery, clinical trials, indications, and molecular mechanisms. For drug resistance, the revealed mechanisms of action and the combination therapies are also discussed. In fact, the known small-molecule-based therapies still have limited clinical benefits to liver cancer patients. Therefore, we analyze the current status and give our ideas for the urgent issues and future directions in this field, suggesting clues for novel techniques in liver cancer treatment.
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Affiliation(s)
- Yue Ming
- Laboratory of Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China
| | - Yanqiu Gong
- National Clinical Research Center for Geriatrics and Department of General Practice, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xuewen Fu
- Jinhua Huanke Environmental Technology Co., Ltd., Jinhua 321000, China
| | - Xinyu Ouyang
- Laboratory of Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China; West China School of Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yong Peng
- Laboratory of Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China; Frontier Medical Center, Tianfu Jincheng Laboratory, Chengdu 610212, China.
| | - Wenchen Pu
- Laboratory of Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China; West China School of Medicine, West China Hospital, Sichuan University, Chengdu 610041, China.
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12
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Wang L, Yao Q, Guo X, Wang B, Si J, Wang X, Jing S, Yan M, Shi Y, Song G, Shen X, Guan J, Zhao Y, Zhu C. Targeted delivery of CEBPA-saRNA for the treatment of pancreatic ductal adenocarcinoma by transferrin receptor aptamer decorated tetrahedral framework nucleic acid. J Nanobiotechnology 2024; 22:392. [PMID: 38965606 PMCID: PMC11223357 DOI: 10.1186/s12951-024-02665-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 06/25/2024] [Indexed: 07/06/2024] Open
Abstract
Pancreatic cancer, predominantly pancreatic ductal adenocarcinoma (PDAC), remains a highly lethal malignancy with limited therapeutic options and a dismal prognosis. By targeting the underlying molecular abnormalities responsible for PDAC development and progression, gene therapy offers a promising strategy to overcome the challenges posed by conventional radiotherapy and chemotherapy. This study sought to explore the therapeutic potential of small activating RNAs (saRNAs) specifically targeting the CCAAT/enhancer-binding protein alpha (CEBPA) gene in PDAC. To overcome the challenges associated with saRNA delivery, tetrahedral framework nucleic acids (tFNAs) were rationally engineered as nanocarriers. These tFNAs were further functionalized with a truncated transferrin receptor aptamer (tTR14) to enhance targeting specificity for PDAC cells. The constructed tFNA-based saRNA formulation demonstrated exceptional stability, efficient saRNA release ability, substantial cellular uptake, biocompatibility, and nontoxicity. In vitro experiments revealed successful intracellular delivery of CEBPA-saRNA utilizing tTR14-decorated tFNA nanocarriers, resulting in significant activation of tumor suppressor genes, namely, CEBPA and its downstream effector P21, leading to notable inhibition of PDAC cell proliferation. Moreover, in a mouse model of PDAC, the tTR14-decorated tFNA-mediated delivery of CEBPA-saRNA effectively upregulated the expression of the CEBPA and P21 genes, consequently suppressing tumor growth. These compelling findings highlight the potential utility of saRNA delivered via a designed tFNA nanocarrier to induce the activation of tumor suppressor genes as an innovative therapeutic approach for PDAC.
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Affiliation(s)
- Li Wang
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China
- College of Clinical Medicine, Changchun University of Chinese Medicine, Changchun, China
- Joint Laboratory of Biomaterials and Translational Medicine, Puheng Technology, Suzhou, China
| | - Qunyan Yao
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Geriatric Medical Center, Shanghai, China
| | - Xuerui Guo
- Department of Experimental Pharmacology and Toxicology, School of Pharmacy, Jilin University, Changchun, China
| | - Bingmei Wang
- College of Clinical Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Jingyi Si
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xingye Wang
- College of Clinical Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Shisong Jing
- State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
| | - Ming Yan
- The Third Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, China
| | - Yan Shi
- Department of Experimental Pharmacology and Toxicology, School of Pharmacy, Jilin University, Changchun, China
| | - Guangqi Song
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China
- Joint Laboratory of Biomaterials and Translational Medicine, Puheng Technology, Suzhou, China
| | - Xizhong Shen
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jiyu Guan
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun, China.
| | - Yicheng Zhao
- China-Japan Union Hospital of Jilin University, Changchun, China.
- College of Clinical Medicine, Changchun University of Chinese Medicine, Changchun, China.
- Joint Laboratory of Biomaterials and Translational Medicine, Puheng Technology, Suzhou, China.
| | - Changfeng Zhu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China.
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13
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Gu S, Huang X, Luo S, Liu Y, Khoong Y, Liang H, Tu L, Xu R, Yang E, Zhao Y, Yao M, Zan T. Targeting the nuclear long noncoding transcript LSP1P5 abrogates extracellular matrix deposition by trans-upregulating CEBPA in keloids. Mol Ther 2024; 32:1984-1999. [PMID: 38553852 PMCID: PMC11184311 DOI: 10.1016/j.ymthe.2024.03.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 01/07/2024] [Accepted: 03/26/2024] [Indexed: 06/09/2024] Open
Abstract
Keloids are characterized by fibroblast hyperproliferation and excessive accumulation of extracellular matrix (ECM) and are a major global health care burden among cutaneous diseases. However, the function of long noncoding RNA (lncRNA)-mediated ECM remodeling during the pathogenesis of keloids is still unclear. Herein, we identified a long noncoding transcript, namely, lymphocyte-specific protein 1 pseudogene 5 (LSP1P5), that modulates ECM component deposition in keloids. First, high-throughput transcriptome analysis showed that LSP1P5 was selectively upregulated in keloids and correlated with more severe disease in a clinical keloid cohort. Therapeutically, the attenuation of LSP1P5 significantly decreased the expression of ECM markers (COL1, COL3, and FN1) both in vitro and in vivo. Intriguingly, an antifibrotic gene, CCAAT enhancer binding protein alpha (CEBPA), is a functional downstream candidate of LSP1P5. Mechanistically, LSP1P5 represses CEBPA expression by hijacking Suppressor of Zeste 12 to the promoter of CEBPA, thereby enhancing the polycomb repressive complex 2-mediated H3K27me3 and changing the chromosomal opening status of CEBPA. Taken together, these findings indicate that targeting LSP1P5 abrogates fibrosis in keloids through epigenetic regulation of CEBPA, revealing a novel antifibrotic therapeutic strategy that bridges our current understanding of lncRNA regulation, histone modification and ECM remodeling in keloids.
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Affiliation(s)
- Shuchen Gu
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, P.R. China
| | - Xin Huang
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, P.R. China
| | - Shenying Luo
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, P.R. China
| | - Yunhan Liu
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, P.R. China
| | - Yimin Khoong
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, P.R. China
| | - Hsin Liang
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, P.R. China
| | - Liying Tu
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, P.R. China
| | - Ruoqing Xu
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, P.R. China
| | - En Yang
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, P.R. China
| | - Yixuan Zhao
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, P.R. China.
| | - Min Yao
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, P.R. China.
| | - Tao Zan
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, P.R. China.
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14
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Bi CQ, Kang T, Qian YK, Kang M, Zeng XH, Li LC. Upregulation of LHPP by saRNA inhibited hepatocellular cancer cell proliferation and xenograft tumor growth. PLoS One 2024; 19:e0299522. [PMID: 38696452 PMCID: PMC11065268 DOI: 10.1371/journal.pone.0299522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 02/13/2024] [Indexed: 05/04/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer worldwide and no pharmacological treatment is available that can achieve complete remission of HCC. Phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) is a recently identified HCC tumor suppressor gene which plays an important role in the development of HCC and its inactivation and reactivation has been shown to result in respectively HCC tumorigenesis and suppression. Small activating RNAs (saRNAs) have been used to achieve targeted activation of therapeutic genes for the restoration of their encoded protein through the RNAa mechanism. Here we designed and validated saRNAs that could activate LHPP expression at both the mRNA and protein levels in HCC cells. Activation of LHPP by its saRNAs led to the suppression of HCC proliferation, migration and the inhibition of Akt phosphorylation. When combined with targeted anticancer drugs (e.g., regorafenib), LHPP saRNA exhibited synergistic effect in inhibiting in vitro HCC proliferation and in vivo antitumor growth in a xenograft HCC model. Findings from this study provides further evidence for a tumor suppressor role of LHPP and potential therapeutic value of restoring the expression of LHPP by saRNA for the treatment of HCC.
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Affiliation(s)
- Chuan-Qian Bi
- Institute of Reproductive Medicine, School of Medicine, Nantong University, Nantong, Jiangsu, China
| | - Tao Kang
- Ractigen Therapeutics, Nantong, Jiangsu, China
| | - Yu-Kang Qian
- Institute of Reproductive Medicine, School of Medicine, Nantong University, Nantong, Jiangsu, China
| | - Moorim Kang
- Ractigen Therapeutics, Nantong, Jiangsu, China
| | - Xu-Hui Zeng
- Institute of Reproductive Medicine, School of Medicine, Nantong University, Nantong, Jiangsu, China
| | - Long-Cheng Li
- Institute of Reproductive Medicine, School of Medicine, Nantong University, Nantong, Jiangsu, China
- Ractigen Therapeutics, Nantong, Jiangsu, China
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15
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Yan T, Yan N, Xia Y, Sawaswong V, Zhu X, Dias HB, Aibara D, Takahashi S, Hamada K, Saito Y, Li G, Liu H, Yan H, Velenosi TJ, Krausz KW, Huang J, Kimura S, Rotman Y, Qu A, Hao H, Gonzalez FJ. Hepatocyte-specific CCAAT/enhancer binding protein α restricts liver fibrosis progression. J Clin Invest 2024; 134:e166731. [PMID: 38557493 PMCID: PMC10977981 DOI: 10.1172/jci166731] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 02/09/2024] [Indexed: 04/04/2024] Open
Abstract
Metabolic dysfunction-associated steatohepatitis (MASH) - previously described as nonalcoholic steatohepatitis (NASH) - is a major driver of liver fibrosis in humans, while liver fibrosis is a key determinant of all-cause mortality in liver disease independent of MASH occurrence. CCAAT/enhancer binding protein α (CEBPA), as a versatile ligand-independent transcriptional factor, has an important function in myeloid cells, and is under clinical evaluation for cancer therapy. CEBPA is also expressed in hepatocytes and regulates glucolipid homeostasis; however, the role of hepatocyte-specific CEBPA in modulating liver fibrosis progression is largely unknown. Here, hepatic CEBPA expression was found to be decreased during MASH progression both in humans and mice, and hepatic CEBPA mRNA was negatively correlated with MASH fibrosis in the human liver. CebpaΔHep mice had markedly enhanced liver fibrosis induced by a high-fat, high-cholesterol, high-fructose diet or carbon tetrachloride. Temporal and spatial hepatocyte-specific CEBPA loss at the progressive stage of MASH in CebpaΔHep,ERT2 mice functionally promoted liver fibrosis. Mechanistically, hepatocyte CEBPA directly repressed Spp1 transactivation to reduce the secretion of osteopontin, a fibrogenesis inducer of hepatic stellate cells. Forced hepatocyte-specific CEBPA expression reduced MASH-associated liver fibrosis. These results demonstrate an important role for hepatocyte-specific CEBPA in liver fibrosis progression, and may help guide the therapeutic discoveries targeting hepatocyte CEBPA for the treatment of liver fibrosis.
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Affiliation(s)
- Tingting Yan
- Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
- State Key Laboratory of Natural Medicines, Laboratory of Metabolic Regulation and Drug Target Discovery, China Pharmaceutical University, Nanjing, China
| | - Nana Yan
- Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
- State Key Laboratory of Natural Medicines, Laboratory of Metabolic Regulation and Drug Target Discovery, China Pharmaceutical University, Nanjing, China
| | - Yangliu Xia
- Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Vorthon Sawaswong
- Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Xinxin Zhu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, and Beijing Key Laboratory of Metabolic Disorder-Related Cardiovascular Diseases, Beijing, China
| | - Henrique Bregolin Dias
- Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Daisuke Aibara
- Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Shogo Takahashi
- Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Keisuke Hamada
- Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Yoshifumi Saito
- Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | | | - Hui Liu
- Department of Pathology, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Hualong Yan
- Cancer and Stem Cell Epigenetics, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute and
| | - Thomas J. Velenosi
- Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Kristopher W. Krausz
- Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Jing Huang
- Cancer and Stem Cell Epigenetics, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute and
| | - Shioko Kimura
- Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Yaron Rotman
- Liver and Energy Metabolism Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
| | - Aijuan Qu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, and Beijing Key Laboratory of Metabolic Disorder-Related Cardiovascular Diseases, Beijing, China
| | - Haiping Hao
- State Key Laboratory of Natural Medicines, Laboratory of Metabolic Regulation and Drug Target Discovery, China Pharmaceutical University, Nanjing, China
| | - Frank J. Gonzalez
- Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
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16
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Hsia T, Chen Y. RNA-encapsulating lipid nanoparticles in cancer immunotherapy: From pre-clinical studies to clinical trials. Eur J Pharm Biopharm 2024; 197:114234. [PMID: 38401743 DOI: 10.1016/j.ejpb.2024.114234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Revised: 01/29/2024] [Accepted: 02/14/2024] [Indexed: 02/26/2024]
Abstract
Nanoparticle-based delivery systems such as RNA-encapsulating lipid nanoparticles (RNA LNPs) have dramatically advanced in function and capacity over the last few decades. RNA LNPs boast of a diverse array of external and core configurations that enhance targeted delivery and prolong circulatory retention, advancing therapeutic outcomes. Particularly within the realm of cancer immunotherapies, RNA LNPs are increasingly gaining prominence. Pre-clinical in vitro and in vivo studies have laid a robust foundation for new and ongoing clinical trials that are actively enrolling patients for RNA LNP cancer immunotherapy. This review explores RNA LNPs, starting from their core composition to their external membrane formulation, set against a backdrop of recent clinical breakthroughs. We further elucidate the LNP delivery avenues, broach the prevailing challenges, and contemplate the future perspectives of RNA LNP-mediated immunotherapy.
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Affiliation(s)
- Tiffaney Hsia
- Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan
| | - Yunching Chen
- Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan; Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan.
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Xia Z, Wei Z, Li X, Liu Y, Gu X, Huang S, Zhang X, Wang W. C/EBPα aggravates renal fibrosis in CKD through the NOX4-ROS-apoptosis pathway in tubular epithelial cells. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167039. [PMID: 38281712 DOI: 10.1016/j.bbadis.2024.167039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2023] [Revised: 01/11/2024] [Accepted: 01/19/2024] [Indexed: 01/30/2024]
Abstract
BACKGROUND Chronic kidney disease (CKD) is a prevalent renal disorder with various risk factors. Emerging evidence indicates that the transcriptional factor CCAAT/enhancer binding protein alpha (C/EBPα) may be associated with renal fibrosis. However, the precise role of C/EBPα in CKD progression remains unexplored. METHODS We investigated the involvement of C/EBPα in CKD using two distinct mouse models induced by folic acid (FA) and unilateral ureteral obstruction (UUO). Additionally, we used RNA sequencing and KEGG analysis to identify potential downstream pathways governed by C/EBPα. FINDINGS Cebpa knockout significantly shielded mice from renal fibrosis and reduced reactive oxygen species (ROS) levels in both the FA and UUO models. Primary tubular epithelial cells (PTECs) lacking Cebpa exhibited reduced apoptosis and ROS accumulation following treatment with TGF-β. RNA sequencing analysis suggested that apoptosis is among the primary pathways regulated by C/EBPα, and identified NADPH oxidoreductase 4 (NOX4) as a key protein upregulated upon C/EBPα induction (ICCB280). Treatment with l-Theanine, a potential NOX4 inhibitor, mitigated renal fibrosis and inflammation in both the FA and UUO mouse models. INTERPRETATION Our study unveils a role for C/EBPα in suppressing renal fibrosis, mitigating ROS accumulation, and reducing cell apoptosis. Furthermore, we investigate whether these protective effects are mediated by C/EBPα's regulation of NOX4 expression. These findings present a promising therapeutic target for modulating ROS and apoptosis in renal tubular cells, potentially offering an approach to treating CKD and other fibrotic diseases.
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Affiliation(s)
- Ziru Xia
- Department of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People's Republic of China; Institute of Nephrology, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Zhaonan Wei
- Department of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People's Republic of China; Institute of Nephrology, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Xin Li
- Department of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People's Republic of China; Institute of Nephrology, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Yunzi Liu
- Department of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People's Republic of China; Institute of Nephrology, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Xiangchen Gu
- Department of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People's Republic of China; Institute of Nephrology, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China; Department of Nephrology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, People's Republic of China
| | - Siyi Huang
- Department of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People's Republic of China; Institute of Nephrology, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Xiaoyue Zhang
- Department of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People's Republic of China; Institute of Nephrology, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Weiming Wang
- Department of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People's Republic of China; Institute of Nephrology, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
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18
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Rehman SU, Ullah N, Zhang Z, Zhen Y, Din AU, Cui H, Wang M. Recent insights into the functions and mechanisms of antisense RNA: emerging applications in cancer therapy and precision medicine. Front Chem 2024; 11:1335330. [PMID: 38274897 PMCID: PMC10809404 DOI: 10.3389/fchem.2023.1335330] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 12/19/2023] [Indexed: 01/27/2024] Open
Abstract
The antisense RNA molecule is a unique DNA transcript consisting of 19-23 nucleotides, characterized by its complementary nature to mRNA. These antisense RNAs play a crucial role in regulating gene expression at various stages, including replication, transcription, and translation. Additionally, artificial antisense RNAs have demonstrated their ability to effectively modulate gene expression in host cells. Consequently, there has been a substantial increase in research dedicated to investigating the roles of antisense RNAs. These molecules have been found to be influential in various cellular processes, such as X-chromosome inactivation and imprinted silencing in healthy cells. However, it is important to recognize that in cancer cells; aberrantly expressed antisense RNAs can trigger the epigenetic silencing of tumor suppressor genes. Moreover, the presence of deletion-induced aberrant antisense RNAs can lead to the development of diseases through epigenetic silencing. One area of drug development worth mentioning is antisense oligonucleotides (ASOs), and a prime example of an oncogenic trans-acting long noncoding RNA (lncRNA) is HOTAIR (HOX transcript antisense RNA). NATs (noncoding antisense transcripts) are dysregulated in many cancers, and researchers are just beginning to unravel their roles as crucial regulators of cancer's hallmarks, as well as their potential for cancer therapy. In this review, we summarize the emerging roles and mechanisms of antisense RNA and explore their application in cancer therapy.
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Affiliation(s)
- Shahab Ur Rehman
- College of Animals Science and Technology Yangzhou University, Yangzhou, China
| | - Numan Ullah
- College of Animals Science and Technology Yangzhou University, Yangzhou, China
| | - Zhenbin Zhang
- College of Animals Science and Technology Yangzhou University, Yangzhou, China
| | - Yongkang Zhen
- College of Animals Nutrition Yangzhou University, Yangzhou, China
| | - Aziz-Ud Din
- Department of Human Genetics, Hazara University Mansehra, Mansehra, Pakistan
| | - Hengmi Cui
- College of Animals Science and Technology Yangzhou University, Yangzhou, China
- Institute of Epigenetics and Epigenomics Yangzhou University, College of Animal Nutrition Yangzhou University, Yangzhou, China
| | - Mengzhi Wang
- College of Animals Science and Technology Yangzhou University, Yangzhou, China
- College of Animals Nutrition Yangzhou University, Yangzhou, China
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19
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Cao Y, Liu H, Lu SS, Jones KA, Govind AP, Jeyifous O, Simmons CQ, Tabatabaei N, Green WN, Holder JL, Tahmasebi S, George AL, Dickinson BC. RNA-based translation activators for targeted gene upregulation. Nat Commun 2023; 14:6827. [PMID: 37884512 PMCID: PMC10603104 DOI: 10.1038/s41467-023-42252-z] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Accepted: 10/04/2023] [Indexed: 10/28/2023] Open
Abstract
Technologies capable of programmable translation activation offer strategies to develop therapeutics for diseases caused by insufficient gene expression. Here, we present "translation-activating RNAs" (taRNAs), a bifunctional RNA-based molecular technology that binds to a specific mRNA of interest and directly upregulates its translation. taRNAs are constructed from a variety of viral or mammalian RNA internal ribosome entry sites (IRESs) and upregulate translation for a suite of target mRNAs. We minimize the taRNA scaffold to 94 nucleotides, identify two translation initiation factor proteins responsible for taRNA activity, and validate the technology by amplifying SYNGAP1 expression, a haploinsufficiency disease target, in patient-derived cells. Finally, taRNAs are suitable for delivery as RNA molecules by lipid nanoparticles (LNPs) to cell lines, primary neurons, and mouse liver in vivo. taRNAs provide a general and compact nucleic acid-based technology to upregulate protein production from endogenous mRNAs, and may open up possibilities for therapeutic RNA research.
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Affiliation(s)
- Yang Cao
- Department of Chemistry, The University of Chicago, Chicago, IL, USA
| | - Huachun Liu
- Department of Chemistry, The University of Chicago, Chicago, IL, USA
| | - Shannon S Lu
- Department of Chemistry, The University of Chicago, Chicago, IL, USA
| | - Krysten A Jones
- Department of Chemistry, The University of Chicago, Chicago, IL, USA
| | - Anitha P Govind
- Department of Neurobiology, The University of Chicago, Chicago, IL, USA
| | - Okunola Jeyifous
- Department of Neurobiology, The University of Chicago, Chicago, IL, USA
| | - Christine Q Simmons
- Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Negar Tabatabaei
- Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, IL, USA
| | - William N Green
- Department of Neurobiology, The University of Chicago, Chicago, IL, USA
| | - Jimmy L Holder
- Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
- Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA
| | - Soroush Tahmasebi
- Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, IL, USA
| | - Alfred L George
- Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Bryan C Dickinson
- Department of Chemistry, The University of Chicago, Chicago, IL, USA.
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20
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Yadav S. Advanced therapeutics avenues in hepatocellular carcinoma: a novel paradigm. Med Oncol 2023; 40:239. [PMID: 37442842 DOI: 10.1007/s12032-023-02104-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 06/21/2023] [Indexed: 07/15/2023]
Abstract
Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer, and it poses a significant risk to patients health and longevity due to its high morbidity and fatality rates. Surgical ablation, radiotherapy, chemotherapy, and, most recently, immunotherapy have all been investigated for HCC, but none have yielded the desired outcomes. Several unique nanocarrier drug delivery techniques have been studied for their potential therapeutic implications in the treatment of HCC. Nanoparticle-based imaging could be effective for more accurate HCC diagnosis. Since its inception, nanomedicine has significantly transformed the approach to both the treatment and diagnostics of liver cancer. Nanoparticles (NPs) are being studied as a potential treatment for liver cancer because of their ability to carry small substances, such as treatment with chemotherapy, microRNA, and therapeutic genes. The primary focus of this study is on the most current discoveries and practical uses of nanomedicine-based diagnostic and therapeutic techniques for liver cancer. In this section, we had gone over what we know about metabolic dysfunction in HCC and the treatment options that attempt to fix it by targeting metabolic pathways. Furthermore, we propose a multi-target metabolic strategy as a viable HCC treatment option. Based on the findings given here, the scientists believe that smart nanomaterials have great promise for improving cancer theranostics and opening up new avenues for tumor diagnosis and treatment.
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Affiliation(s)
- Shikha Yadav
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Plot No.2, Sector 17-A, Yamuna Expressway, Gautam Buddhnagar, Greater Noida, Uttar Pradesh, 201310, India.
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21
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Baker A, Lorch J, VanderWeele D, Zhang B. Smart Nanocarriers for the Targeted Delivery of Therapeutic Nucleic Acid for Cancer Immunotherapy. Pharmaceutics 2023; 15:1743. [PMID: 37376190 DOI: 10.3390/pharmaceutics15061743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 06/09/2023] [Accepted: 06/13/2023] [Indexed: 06/29/2023] Open
Abstract
A wide variety of therapeutic approaches and technologies for delivering therapeutic agents have been investigated for treating cancer. Recently, immunotherapy has achieved success in cancer treatment. Successful clinical results of immunotherapeutic approaches for cancer treatment were led by antibodies targeting immune checkpoints, and many have advanced through clinical trials and obtained FDA approval. A major opportunity remains for the development of nucleic acid technology for cancer immunotherapy in the form of cancer vaccines, adoptive T-cell therapies, and gene regulation. However, these therapeutic approaches face many challenges related to their delivery to target cells, including their in vivo decay, the limited uptake by target cells, the requirements for nuclear penetration (in some cases), and the damage caused to healthy cells. These barriers can be avoided and resolved by utilizing advanced smart nanocarriers (e.g., lipids, polymers, spherical nucleic acids, metallic nanoparticles) that enable the efficient and selective delivery of nucleic acids to the target cells and/or tissues. Here, we review studies that have developed nanoparticle-mediated cancer immunotherapy as a technology for cancer patients. Moreover, we also investigate the crosstalk between the function of nucleic acid therapeutics in cancer immunotherapy, and we discuss how nanoparticles can be functionalized and designed to target the delivery and thus improve the efficacy, toxicity, and stability of these therapeutics.
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Affiliation(s)
- Abu Baker
- Department of Medicine, Hematology/Oncology Division, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Jochen Lorch
- Department of Medicine, Hematology/Oncology Division, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - David VanderWeele
- Department of Medicine, Hematology/Oncology Division, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Bin Zhang
- Department of Medicine, Hematology/Oncology Division, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
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22
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Jiang T, Gonzalez KM, Cordova LE, Lu J. Nanotechnology-enabled gene delivery for cancer and other genetic diseases. Expert Opin Drug Deliv 2023; 20:523-540. [PMID: 37017558 PMCID: PMC10164135 DOI: 10.1080/17425247.2023.2200246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 04/04/2023] [Indexed: 04/06/2023]
Abstract
INTRODUCTION Despite gene therapy is ideal for genetic abnormality-related diseases, the easy degradation, poor targeting, and inefficiency in entering targeted cells are plaguing the effective delivery of gene therapy. Viral and non-viral vectors have been used for delivering gene therapeutics in vivo by safeguarding nucleic acid agents to target cells and to reach the specific intracellular location. A variety of nanotechnology-enabled safe and efficient systems have been successfully developed to improve the targeting ability for effective therapeutic delivery of genetic drugs. AREAS COVERED In this review, we outline the multiple biological barriers associated with gene delivery process, and highlight recent advances to gene therapy strategy in vivo, including gene correction, gene silencing, gene activation and genome editing. We point out current developments and challenges exist of non-viral and viral vector systems in association with chemical and physical gene delivery technologies and their potential for the future. EXPERT OPINION This review focuses on the opportunities and challenges to various gene therapy strategy, with specific emphasis on overcoming the challenges through the development of biocompatibility and smart gene vectors for potential clinical application.
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Affiliation(s)
- Tong Jiang
- Skaggs Pharmaceutical Sciences Center, Department of Pharmacology & Toxicology, R. Ken Coit College of Pharmacy, The University of Arizona, Tucson, Arizona, 85721, United States
| | - Karina Marie Gonzalez
- Skaggs Pharmaceutical Sciences Center, Department of Pharmacology & Toxicology, R. Ken Coit College of Pharmacy, The University of Arizona, Tucson, Arizona, 85721, United States
| | - Leyla Estrella Cordova
- Skaggs Pharmaceutical Sciences Center, Department of Pharmacology & Toxicology, R. Ken Coit College of Pharmacy, The University of Arizona, Tucson, Arizona, 85721, United States
| | - Jianqin Lu
- Skaggs Pharmaceutical Sciences Center, Department of Pharmacology & Toxicology, R. Ken Coit College of Pharmacy, The University of Arizona, Tucson, Arizona, 85721, United States
- NCI-designated University of Arizona Comprehensive Cancer Center, Tucson, Arizona, 85721, United States
- BIO5 Institute, The University of Arizona, Tucson, Arizona, 85721, United States
- Southwest Environmental Health Sciences Center, The University of Arizona, Tucson, 85721, United States
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23
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Singh S, Sharma N, Shukla S, Behl T, Gupta S, Anwer MK, Vargas-De-La-Cruz C, Bungau SG, Brisc C. Understanding the Potential Role of Nanotechnology in Liver Fibrosis: A Paradigm in Therapeutics. Molecules 2023; 28:molecules28062811. [PMID: 36985782 PMCID: PMC10057127 DOI: 10.3390/molecules28062811] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Revised: 03/15/2023] [Accepted: 03/17/2023] [Indexed: 03/30/2023] Open
Abstract
The liver is a vital organ that plays a crucial role in the physiological operation of the human body. The liver controls the body's detoxification processes as well as the storage and breakdown of red blood cells, plasma protein and hormone production, and red blood cell destruction; therefore, it is vulnerable to their harmful effects, making it more prone to illness. The most frequent complications of chronic liver conditions include cirrhosis, fatty liver, liver fibrosis, hepatitis, and illnesses brought on by alcohol and drugs. Hepatic fibrosis involves the activation of hepatic stellate cells to cause persistent liver damage through the accumulation of cytosolic matrix proteins. The purpose of this review is to educate a concise discussion of the epidemiology of chronic liver disease, the pathogenesis and pathophysiology of liver fibrosis, the symptoms of liver fibrosis progression and regression, the clinical evaluation of liver fibrosis and the research into nanotechnology-based synthetic and herbal treatments for the liver fibrosis is summarized in this article. The herbal remedies summarized in this review article include epigallocathechin-3-gallate, silymarin, oxymatrine, curcumin, tetrandrine, glycyrrhetinic acid, salvianolic acid, plumbagin, Scutellaria baicalnsis Georgi, astragalosides, hawthorn extract, and andrographolides.
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Affiliation(s)
- Sukhbir Singh
- Department of Pharmaceutics, MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala 133207, Haryana, India
| | - Neelam Sharma
- Department of Pharmaceutics, MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala 133207, Haryana, India
| | - Saurabh Shukla
- Chitkara College of Pharmacy, Chitkara University, Punjab 140401, India
| | - Tapan Behl
- School of Health Sciences &Technology, University of Petroleum and Energy Studies, Dehradun 248007, Uttarakhand, India
| | - Sumeet Gupta
- Department of Pharmacology, MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala 133207, Haryana, India
| | - Md Khalid Anwer
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj 11942, Saudi Arabia
| | - Celia Vargas-De-La-Cruz
- Department of Pharmacology, Bromatology and Toxicology, Faculty of Pharmacy and Biochemistry, Universidad Nacional Mayor de San Marcos, Lima 150001, Peru
- E-Health Research Center, Universidad de Ciencias y Humanidades, Lima 15001, Peru
| | - Simona Gabriela Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania
- Doctoral School of Biomedical Sciences, University of Oradea, 410087 Oradea, Romania
| | - Cristina Brisc
- Department of Medical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania
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24
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Sufian MA, Ilies MA. Lipid-based nucleic acid therapeutics with in vivo efficacy. WILEY INTERDISCIPLINARY REVIEWS. NANOMEDICINE AND NANOBIOTECHNOLOGY 2023; 15:e1856. [PMID: 36180107 PMCID: PMC10023279 DOI: 10.1002/wnan.1856] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 07/22/2022] [Accepted: 08/30/2022] [Indexed: 03/09/2023]
Abstract
Synthetic vectors for therapeutic nucleic acid delivery are currently competing significantly with their viral counter parts due to their reduced immunogenicity, large payload capacity, and ease of manufacture under GMP-compliant norms. The approval of Onpattro, a lipid-based siRNA therapeutic, and the proven clinical success of two lipid-based COVID-19 vaccines from Pfizer-BioNTech, and Moderna heralded the specific advantages of lipid-based systems among all other synthetic nucleic acid carriers. Lipid-based systems with diverse payloads-plasmid DNA (pDNA), antisense oligonucleotide (ASO), small interfering RNA (siRNA), microRNA (miRNA), small activating RNA (saRNA), and messenger RNA (mRNA)-are now becoming a mature technology, with growing impact in the clinic. Research over four decades identified the key factors determining the therapeutic success of these multi-component systems. Here, we discuss the main nucleic acid-based technologies, presenting their mechanism of action, delivery barriers facing them, the structural properties of the payload as well as the component lipids that regulate physicochemical properties, pharmacokinetics and biodistribution, efficacy, and toxicity of the resultant nanoparticles. We further detail on the formulation parameters, evolution of the manufacturing techniques that generate reproducible and scalable outputs, and key manufacturing aspects that enable control over physicochemical properties of the resultant particles. Preclinical applications of some of these formulations that were successfully translated from in vitro studies to animal models are subsequently discussed. Finally, clinical success and failure of these systems starting from 1993 to present are highlighted, in a holistic literature review focused on lipid-based nucleic acid delivery systems. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials.
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Affiliation(s)
- Md Abu Sufian
- Department of Pharmaceutical Sciences and Moulder Center for Drug Discovery Research, School of Pharmacy, Temple University, 3307 North Broad Street, Philadelphia, PA 19140, USA
| | - Marc A. Ilies
- Department of Pharmaceutical Sciences and Moulder Center for Drug Discovery Research, School of Pharmacy, Temple University, 3307 North Broad Street, Philadelphia, PA 19140, USA
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25
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Roth C, Kilpinen H, Kurian MA, Barral S. Histone lysine methyltransferase-related neurodevelopmental disorders: current knowledge and saRNA future therapies. Front Cell Dev Biol 2023; 11:1090046. [PMID: 36923252 PMCID: PMC10009263 DOI: 10.3389/fcell.2023.1090046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Accepted: 02/06/2023] [Indexed: 03/02/2023] Open
Abstract
Neurodevelopmental disorders encompass a group of debilitating diseases presenting with motor and cognitive dysfunction, with variable age of onset and disease severity. Advances in genetic diagnostic tools have facilitated the identification of several monogenic chromatin remodeling diseases that cause Neurodevelopmental disorders. Chromatin remodelers play a key role in the neuro-epigenetic landscape and regulation of brain development; it is therefore not surprising that mutations, leading to loss of protein function, result in aberrant neurodevelopment. Heterozygous, usually de novo mutations in histone lysine methyltransferases have been described in patients leading to haploinsufficiency, dysregulated protein levels and impaired protein function. Studies in animal models and patient-derived cell lines, have highlighted the role of histone lysine methyltransferases in the regulation of cell self-renewal, cell fate specification and apoptosis. To date, in depth studies of histone lysine methyltransferases in oncology have provided strong evidence of histone lysine methyltransferase dysregulation as a determinant of cancer progression and drug resistance. As a result, histone lysine methyltransferases have become an important therapeutic target for the treatment of different cancer forms. Despite recent advances, we still lack knowledge about the role of histone lysine methyltransferases in neuronal development. This has hampered both the study and development of precision therapies for histone lysine methyltransferases-related Neurodevelopmental disorders. In this review, we will discuss the current knowledge of the role of histone lysine methyltransferases in neuronal development and disease progression. We will also discuss how RNA-based technologies using small-activating RNAs could potentially provide a novel therapeutic approach for the future treatment of histone lysine methyltransferase haploinsufficiency in these Neurodevelopmental disorders, and how they could be first tested in state-of-the-art patient-derived neuronal models.
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Affiliation(s)
- Charlotte Roth
- Molecular Neurosciences, Developmental Neurosciences Programme, Zayed Centre for Research into Rare Disease in Children, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
| | - Helena Kilpinen
- Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
- Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland
| | - Manju A. Kurian
- Molecular Neurosciences, Developmental Neurosciences Programme, Zayed Centre for Research into Rare Disease in Children, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
- Department of Neurology, Great Ormond Street Hospital for Children, London, United Kingdom
| | - Serena Barral
- Molecular Neurosciences, Developmental Neurosciences Programme, Zayed Centre for Research into Rare Disease in Children, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
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26
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Goswami S, Anandhan S, Raychaudhuri D, Sharma P. Myeloid cell-targeted therapies for solid tumours. Nat Rev Immunol 2023; 23:106-120. [PMID: 35697799 DOI: 10.1038/s41577-022-00737-w] [Citation(s) in RCA: 109] [Impact Index Per Article: 54.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/12/2022] [Indexed: 02/04/2023]
Abstract
Myeloid cells are the most abundant immune components of the tumour microenvironment, where they have a variety of functions, ranging from immunosuppressive to immunostimulatory roles. The myeloid cell compartment comprises many different cell types, including monocytes, macrophages, dendritic cells and granulocytes, that are highly plastic and can differentiate into diverse phenotypes depending on cues received from their microenvironment. In the past few decades, we have gained a better appreciation of the complexity of myeloid cell subsets and how they are involved in tumour progression and resistance to cancer therapies, including immunotherapy. In this Review, we highlight key features of monocyte and macrophage biology that are being explored as potential targets for cancer therapies and what aspects of myeloid cells need a deeper understanding to identify rational combinatorial strategies to improve clinical outcomes of patients with cancer. We discuss therapies that aim to modulate the functional activities of myeloid cell populations, impacting their recruitment, survival and activity in the tumour microenvironment, acting at the level of cell surface receptors, signalling pathways, epigenetic machinery and metabolic regulators. We also describe advances in the development of genetically engineered myeloid cells for cancer therapy.
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Affiliation(s)
- Sangeeta Goswami
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.,Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Swetha Anandhan
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.,MD Anderson UT Health Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Deblina Raychaudhuri
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Padmanee Sharma
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. .,Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. .,The Immunotherapy Platform, The University of Texas MD Anderson Cancer, Center, Houston, TX, USA.
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27
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RNA therapeutics: updates and future potential. SCIENCE CHINA. LIFE SCIENCES 2023; 66:12-30. [PMID: 36100838 PMCID: PMC9470505 DOI: 10.1007/s11427-022-2171-2] [Citation(s) in RCA: 68] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 07/17/2022] [Indexed: 02/04/2023]
Abstract
Recent advancements in the production, modification, and cellular delivery of RNA molecules facilitated the expansion of RNA-based therapeutics. The increasing understanding of RNA biology initiated a corresponding growth in RNA therapeutics. In this review, the general concepts of five classes of RNA-based therapeutics, including RNA interference-based therapies, antisense oligonucleotides, small activating RNA therapies, circular RNA therapies, and messenger RNA-based therapeutics, will be discussed. Moreover, we also provide an overview of RNA-based therapeutics that have already received regulatory approval or are currently being evaluated in clinical trials, along with challenges faced by these technologies. RNA-based drugs demonstrated positive clinical trial results and have the ability to address previously "undruggable" targets, which delivers great promise as a disruptive therapeutic technology to fulfill its full clinical potentiality.
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28
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Gregory GL, Copple IM. Modulating the expression of tumor suppressor genes using activating oligonucleotide technologies as a therapeutic approach in cancer. MOLECULAR THERAPY. NUCLEIC ACIDS 2022; 31:211-223. [PMID: 36700046 PMCID: PMC9840112 DOI: 10.1016/j.omtn.2022.12.016] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Tumor suppressor genes (TSGs) are frequently downregulated in cancer, leading to dysregulation of the pathways that they control. The continuum model of tumor suppression suggests that even subtle changes in TSG expression, for example, driven by epigenetic modifications or copy number alterations, can lead to a loss of gene function and a phenotypic effect. This approach to exploring tumor suppression provides opportunities for alternative therapies that may be able to restore TSG expression toward normal levels, such as oligonucleotide therapies. Oligonucleotide therapies involve the administration of exogenous nucleic acids to modulate the expression of specific endogenous genes. This review focuses on two types of activating oligonucleotide therapies, small-activating RNAs and synthetic mRNAs, as novel methods to increase the expression of TSGs in cancer.
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Affiliation(s)
- Georgina L. Gregory
- Department of Pharmacology & Therapeutics, Institute of Systems, Molecular & Integrative Biology, University of Liverpool, Liverpool L69 3GE, UK
| | - Ian M. Copple
- Department of Pharmacology & Therapeutics, Institute of Systems, Molecular & Integrative Biology, University of Liverpool, Liverpool L69 3GE, UK
- Corresponding author: Department of Pharmacology & Therapeutics, Institute of Systems, Molecular & Integrative Biology, University of Liverpool, Liverpool L69 3GE, UK.
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29
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Andrikakou P, Reebye V, Vasconcelos D, Yoon S, Voutila J, George AJT, Swiderski P, Habib R, Catley M, Blakey D, Habib NA, Rossi JJ, Huang KW. Enhancing SIRT1 Gene Expression Using Small Activating RNAs: A Novel Approach for Reversing Metabolic Syndrome. Nucleic Acid Ther 2022; 32:486-496. [PMID: 35895511 DOI: 10.1089/nat.2021.0115] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Metabolic syndrome (MetS) is a pathological condition characterized by abdominal obesity, insulin resistance, hypertension, and hyperlipidemia. Sirtuin 1 (SIRT1), a highly conserved histone deacetylase, is characterized as a key metabolic regulator and protector against aging-associated pathologies, including MetS. In this study, we investigate the therapeutic potential of activating SIRT1 using small activating RNAs (saRNA), thereby reducing inflammatory-like responses and re-establishing normal lipid metabolism. SIRT1 saRNA significantly increased SIRT1 messenger RNA (mRNA) and protein levels in both lipopolysaccharide-stimulated and nonstimulated macrophages. SIRT1 saRNA significantly decreased inflammatory-like responses, by reducing mRNA levels of key inflammatory cytokines, such as Tumor Necrosis Factor alpha, Interleukin 1 beta (IL-1β), Interleukin 6 (IL-6), and chemokines Monocyte Chemoattractant Protein-1 and keratinocyte chemoattractant. SIRT1 overexpression also significantly reduced phosphorylation of nuclear factor-κB and c-Jun N-terminal kinase, both key signaling molecules for the inflammatory pathway. To investigate the therapeutic effect of SIRT1 upregulation, we treated a high-fat diet model with SIRT1 saRNA conjugated to a transferrin receptor aptamer for delivery to the liver and cellular internalization. Animals in the SIRT1 saRNA treatment arm demonstrated significantly decreased weight gain with a significant reduction in white adipose tissue, triglycerides, fasting glucose levels, and intracellular lipid accumulation. These suggest treatment-induced changes to lipid and glucose metabolism in the animals. The results of this study demonstrate that targeted activation of SIRT1 by saRNAs is a potential strategy to reverse MetS.
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Affiliation(s)
- Pinelopi Andrikakou
- Department of Surgery and Cancer, Imperial College London, London, United Kingdom
| | - Vikash Reebye
- Department of Surgery and Cancer, Imperial College London, London, United Kingdom
| | - Daniel Vasconcelos
- MiNA Therapeutics Limited, London, United Kingdom
- Center for Drug Discovery and Innovative Medicines (MedInUP), University of Porto, Porto, Portugal
| | - Sorah Yoon
- Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, Duarte, California, USA
| | - Jon Voutila
- MiNA Therapeutics Limited, London, United Kingdom
| | | | - Piotr Swiderski
- DNA/RNA Synthesis Core Facility, Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, California, USA
| | - Robert Habib
- MiNA Therapeutics Limited, London, United Kingdom
| | | | - David Blakey
- MiNA Therapeutics Limited, London, United Kingdom
| | - Nagy A Habib
- Department of Surgery and Cancer, Imperial College London, London, United Kingdom
- MiNA Therapeutics Limited, London, United Kingdom
| | - John J Rossi
- Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, Duarte, California, USA
| | - Kai-Wen Huang
- Department of Surgery, Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan
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30
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Gárate-Rascón M, Recalde M, Rojo C, Fernández-Barrena MG, Ávila MA, Arechederra M, Berasain C. SLU7: A New Hub of Gene Expression Regulation—From Epigenetics to Protein Stability in Health and Disease. Int J Mol Sci 2022; 23:ijms232113411. [PMID: 36362191 PMCID: PMC9658179 DOI: 10.3390/ijms232113411] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 10/28/2022] [Accepted: 10/31/2022] [Indexed: 11/06/2022] Open
Abstract
SLU7 (Splicing factor synergistic lethal with U5 snRNA 7) was first identified as a splicing factor necessary for the correct selection of 3′ splice sites, strongly impacting on the diversity of gene transcripts in a cell. More recent studies have uncovered new and non-redundant roles of SLU7 as an integrative hub of different levels of gene expression regulation, including epigenetic DNA remodeling, modulation of transcription and protein stability. Here we review those findings, the multiple factors and mechanisms implicated as well as the cellular functions affected. For instance, SLU7 is essential to secure liver differentiation, genome integrity acting at different levels and a correct cell cycle progression. Accordingly, the aberrant expression of SLU7 could be associated with human diseases including cancer, although strikingly, it is an essential survival factor for cancer cells. Finally, we discuss the implications of SLU7 in pathophysiology, with particular emphasis on the progression of liver disease and its possible role as a therapeutic target in human cancer.
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Affiliation(s)
- María Gárate-Rascón
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Avda. Pio XII, n55, 31008 Pamplona, Spain
| | - Miriam Recalde
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Avda. Pio XII, n55, 31008 Pamplona, Spain
| | - Carla Rojo
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Avda. Pio XII, n55, 31008 Pamplona, Spain
| | - Maite G. Fernández-Barrena
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Avda. Pio XII, n55, 31008 Pamplona, Spain
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain
| | - Matías A. Ávila
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Avda. Pio XII, n55, 31008 Pamplona, Spain
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain
| | - María Arechederra
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Avda. Pio XII, n55, 31008 Pamplona, Spain
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain
| | - Carmen Berasain
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Avda. Pio XII, n55, 31008 Pamplona, Spain
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain
- Correspondence: ; Tel.: +34-948-194700; Fax: +34-948-194717
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Xiong Y, Ke R, Zhang Q, Lan W, Yuan W, Chan KNI, Roussel T, Jiang Y, Wu J, Liu S, Wong AST, Shim JS, Zhang X, Xie R, Dusetti N, Iovanna J, Habib N, Peng L, Lee LTO. Small Activating RNA Modulation of the G Protein-Coupled Receptor for Cancer Treatment. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2200562. [PMID: 35712764 PMCID: PMC9475523 DOI: 10.1002/advs.202200562] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 05/23/2022] [Indexed: 06/15/2023]
Abstract
G protein-coupled receptors (GPCRs) are the most common and important drug targets. However, >70% of GPCRs are undruggable or difficult to target using conventional chemical agonists/antagonists. Small nucleic acid molecules, which can sequence-specifically modulate any gene, offer a unique opportunity to effectively expand drug targets, especially those that are undruggable or difficult to address, such as GPCRs. Here, the authors report for the first time that small activating RNAs (saRNAs) effectively modulate a GPCR for cancer treatment. Specifically, saRNAs promoting the expression of Mas receptor (MAS1), a GPCR that counteracts the classical angiotensin II pathway in cancer cell proliferation and migration, are identified. These saRNAs, delivered by an amphiphilic dendrimer vector, enhance MAS1 expression, counteracting the angiotensin II/angiotensin II Receptor Type 1 axis, and leading to significant suppression of tumorigenesis and the inhibition of tumor progression of multiple cancers in tumor-xenografted mouse models and patient-derived tumor models. This study provides not only a new strategy for cancer therapy by targeting the renin-angiotensin system, but also a new avenue to modulate GPCR signaling by RNA activation.
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Affiliation(s)
- Yunfang Xiong
- Cancer CentreFaculty of Health SciencesUniversity of MacauTaipaMacau999078China
| | - Ran Ke
- Cancer CentreFaculty of Health SciencesUniversity of MacauTaipaMacau999078China
| | - Qingyu Zhang
- Department of Obstetrics and GynaecologyAffiliated Hospital of Guangdong Medical UniversityZhanjiangGuangdong524001China
| | - Wenjun Lan
- Aix Marseille UniversitéCNRSCentre Interdisciplinaire de Nanoscience de Marseille (UMR 7325)Equipe Labellisée Ligue Contre le CancerMarseille13288France
- Centre de Recherche en Cancérologie de Marseille (CRCM)INSERM U1068CNRSAix‐Marseille Université and Institut Paoli‐CalmettesMarseille13288France
| | - Wanjun Yuan
- Cancer CentreFaculty of Health SciencesUniversity of MacauTaipaMacau999078China
| | - Karol Nga Ieng Chan
- Cancer CentreFaculty of Health SciencesUniversity of MacauTaipaMacau999078China
| | - Tom Roussel
- Aix Marseille UniversitéCNRSCentre Interdisciplinaire de Nanoscience de Marseille (UMR 7325)Equipe Labellisée Ligue Contre le CancerMarseille13288France
| | - Yifan Jiang
- Aix Marseille UniversitéCNRSCentre Interdisciplinaire de Nanoscience de Marseille (UMR 7325)Equipe Labellisée Ligue Contre le CancerMarseille13288France
| | - Jing Wu
- Aix Marseille UniversitéCNRSCentre Interdisciplinaire de Nanoscience de Marseille (UMR 7325)Equipe Labellisée Ligue Contre le CancerMarseille13288France
| | - Shuai Liu
- Cancer CentreFaculty of Health SciencesUniversity of MacauTaipaMacau999078China
| | - Alice Sze Tsai Wong
- School of Biological SciencesThe University of Hong KongPokfulam RoadHong KongChina
| | - Joong Sup Shim
- Cancer CentreFaculty of Health SciencesUniversity of MacauTaipaMacau999078China
- MOE Frontiers Science Center for Precision OncologyUniversity of MacauTaipaMacau999078China
| | - Xuanjun Zhang
- Cancer CentreFaculty of Health SciencesUniversity of MacauTaipaMacau999078China
- MOE Frontiers Science Center for Precision OncologyUniversity of MacauTaipaMacau999078China
| | - Ruiyu Xie
- Cancer CentreFaculty of Health SciencesUniversity of MacauTaipaMacau999078China
- MOE Frontiers Science Center for Precision OncologyUniversity of MacauTaipaMacau999078China
| | - Nelson Dusetti
- Centre de Recherche en Cancérologie de Marseille (CRCM)INSERM U1068CNRSAix‐Marseille Université and Institut Paoli‐CalmettesMarseille13288France
| | - Juan Iovanna
- Centre de Recherche en Cancérologie de Marseille (CRCM)INSERM U1068CNRSAix‐Marseille Université and Institut Paoli‐CalmettesMarseille13288France
| | - Nagy Habib
- Department of Surgery and CancerImperial College LondonLondonW12 0NNUK
- MiNA Therapeutics, Translation & Innovation Hub80 Wood LaneLondonW12 0BZUK
| | - Ling Peng
- Aix Marseille UniversitéCNRSCentre Interdisciplinaire de Nanoscience de Marseille (UMR 7325)Equipe Labellisée Ligue Contre le CancerMarseille13288France
| | - Leo Tsz On Lee
- Cancer CentreFaculty of Health SciencesUniversity of MacauTaipaMacau999078China
- MOE Frontiers Science Center for Precision OncologyUniversity of MacauTaipaMacau999078China
- Centre of Reproduction, Development, and AgingFaculty of Health SciencesUniversity of MacauTaipaMacau999078China
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32
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Liu A, Han N, Munoz-Muriedas J, Bender A. Deriving time-concordant event cascades from gene expression data: A case study for Drug-Induced Liver Injury (DILI). PLoS Comput Biol 2022; 18:e1010148. [PMID: 35687583 PMCID: PMC9292124 DOI: 10.1371/journal.pcbi.1010148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 07/18/2022] [Accepted: 04/26/2022] [Indexed: 01/10/2023] Open
Abstract
Adverse event pathogenesis is often a complex process which compromises multiple events ranging from the molecular to the phenotypic level. In toxicology, Adverse Outcome Pathways (AOPs) aim to formalize this as temporal sequences of events, in which event relationships should be supported by causal evidence according to the tailored Bradford-Hill criteria. One of the criteria is whether events are consistently observed in a certain temporal order and, in this work, we study this time concordance using the concept of “first activation” as data-driven means to generate hypotheses on potentially causal mechanisms. As a case study, we analysed liver data from repeat-dose studies in rats from the TG-GATEs database which comprises measurements across eight timepoints, ranging from 3 hours to 4 weeks post-treatment. We identified time-concordant gene expression-derived events preceding adverse histopathology, which serves as surrogate readout for Drug-Induced Liver Injury (DILI). We find known mechanisms in DILI to be time-concordant, and show further that significance, frequency and log fold change (logFC) of differential expression are metrics which can additionally prioritize events although not necessary to be mechanistically relevant. Moreover, we used the temporal order of transcription factor (TF) expression and regulon activity to identify transcriptionally regulated TFs and subsequently combined this with prior knowledge on functional interactions to derive detailed gene-regulatory mechanisms, such as reduced Hnf4a activity leading to decreased expression and activity of Cebpa. At the same time, also potentially novel events are identified such as Sox13 which is highly significantly time-concordant and shows sustained activation over time. Overall, we demonstrate how time-resolved transcriptomics can derive and support mechanistic hypotheses by quantifying time concordance and how this can be combined with prior causal knowledge, with the aim of both understanding mechanisms of toxicity, as well as potential applications to the AOP framework. We make our results available in the form of a Shiny app (https://anikaliu.shinyapps.io/dili_cascades), which allows users to query events of interest in more detail. Understanding mechanisms from systems-scale biological data is of great relevance in toxicology as well as drug discovery; however how to generate causal hypotheses instead of correlations is by no means clear. In this work, we study the conserved temporal order of events and present an automatable framework to quantify and characterize time concordance across a large set of time-series. We apply this concept to events derived from time-resolved gene expression and histopathology from the TG-GATEs in vivo liver data as a case study. We were able to recover known events involved in the pathogenesis of Drug-Induced Liver Injury (DILI), and identify potentially novel pathway and transcription factors (TFs) which precede adverse histopathology. As complementary sources of evidence for causality, we additionally show how time concordance and prior knowledge on plausible interactions between TFs can be combined to derive causal hypotheses on the TFs’ mode of regulation and interaction partners. Overall, the results derived in our case study can serve as valuable hypothesis-free starting points for the development of Adverse Outcome Pathways for DILI, and demonstrate that our approach provides a novel angle to prioritize mechanistically relevant events.
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Affiliation(s)
- Anika Liu
- Milner Therapeutics Institute, University of Cambridge, Cambridge, United Kingdom
- Systems Modelling and Translational Biology, Data and Computational Sciences, GSK, London, United Kingdom
- Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Cambridge, United Kingdom
- * E-mail: (AL); (AB)
| | - Namshik Han
- Milner Therapeutics Institute, University of Cambridge, Cambridge, United Kingdom
- Cambridge Centre for AI in Medicine, Department of Applied Mathematics and Theoretical Physics, University of Cambridge, Cambridge, United Kingdom
| | - Jordi Munoz-Muriedas
- Systems Modelling and Translational Biology, Data and Computational Sciences, GSK, London, United Kingdom
- Computer-Aided Drug Design, UCB, Slough, United Kingdom
| | - Andreas Bender
- Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Cambridge, United Kingdom
- * E-mail: (AL); (AB)
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Van Simaeys D, De La Fuente A, Zilio S, Zoso A, Kuznetsova V, Alcazar O, Buchwald P, Grilli A, Caroli J, Bicciato S, Serafini P. RNA aptamers specific for transmembrane p24 trafficking protein 6 and Clusterin for the targeted delivery of imaging reagents and RNA therapeutics to human β cells. Nat Commun 2022; 13:1815. [PMID: 35383192 PMCID: PMC8983715 DOI: 10.1038/s41467-022-29377-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Accepted: 03/08/2022] [Indexed: 12/20/2022] Open
Abstract
The ability to detect and target β cells in vivo can substantially refine how diabetes is studied and treated. However, the lack of specific probes still hampers a precise characterization of human β cell mass and the delivery of therapeutics in clinical settings. Here, we report the identification of two RNA aptamers that specifically and selectively recognize mouse and human β cells. The putative targets of the two aptamers are transmembrane p24 trafficking protein 6 (TMED6) and clusterin (CLUS). When given systemically in immune deficient mice, these aptamers recognize the human islet graft producing a fluorescent signal proportional to the number of human islets transplanted. These aptamers cross-react with endogenous mouse β cells and allow monitoring the rejection of mouse islet allografts. Finally, once conjugated to saRNA specific for X-linked inhibitor of apoptosis (XIAP), they can efficiently transfect non-dissociated human islets, prevent early graft loss, and improve the efficacy of human islet transplantation in immunodeficient in mice.
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Affiliation(s)
- Dimitri Van Simaeys
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Adriana De La Fuente
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Serena Zilio
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Alessia Zoso
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Victoria Kuznetsova
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Oscar Alcazar
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Peter Buchwald
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Andrea Grilli
- Center for Genome Research, Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Jimmy Caroli
- Center for Genome Research, Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Silvio Bicciato
- Center for Genome Research, Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Paolo Serafini
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL, USA. .,Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL, USA. .,Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA.
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34
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Geh D, Leslie J, Rumney R, Reeves HL, Bird TG, Mann DA. Neutrophils as potential therapeutic targets in hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2022; 19:257-273. [PMID: 35022608 DOI: 10.1038/s41575-021-00568-5] [Citation(s) in RCA: 126] [Impact Index Per Article: 42.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/06/2021] [Indexed: 12/13/2022]
Abstract
The success of atezolizumab plus bevacizumab treatment contributed to a shift in systemic therapies for hepatocellular carcinoma (HCC) towards combinations that include cancer immunotherapeutic agents. Thus far, the principal focus of cancer immunotherapy has been on interrupting immune checkpoints that suppress antitumour lymphocytes. As well as lymphocytes, the HCC environment includes numerous other immune cell types, among which neutrophils are emerging as an important contributor to the pathogenesis of HCC. A growing body of evidence supports neutrophils as key mediators of the immunosuppressive environment in which some cancers develop, as well as drivers of tumour progression. If neutrophils have a similar role in HCC, approaches that target or manipulate neutrophils might have therapeutic benefits, potentially including sensitization of tumours to conventional immunotherapy. Several neutrophil-directed therapies for patients with HCC (and other cancers) are now entering clinical trials. This Review outlines the evidence in support of neutrophils as drivers of HCC and details their mechanistic roles in development, progression and metastasis, highlighting the reasons that neutrophils are well worth investigating despite the challenges associated with studying them. Neutrophil-modulating anticancer therapies entering clinical trials are also summarized.
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Affiliation(s)
- Daniel Geh
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Jack Leslie
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Rob Rumney
- School of Pharmacy, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Helen L Reeves
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- The Liver Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK
- Hepatopancreatobiliary Multidisciplinary Team, Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK
| | - Thomas G Bird
- Cancer Research UK Beatson Institute, Glasgow, UK
- MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK
| | - Derek A Mann
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
- Department of Gastroenterology and Hepatology, School of Medicine, Koç University, Istanbul, Turkey.
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35
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Zhang YL, Kang M, Wu JC, Xie MY, Xue RY, Tang Q, Yang H, Li LC. Small activating RNA activation of ATOH1 promotes regeneration of human inner ear hair cells. Bioengineered 2022; 13:6729-6739. [PMID: 35246011 PMCID: PMC8974106 DOI: 10.1080/21655979.2022.2045835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022] Open
Abstract
The loss of inner ear hair cells leads to irreversible acoustic injury in mammals, and regeneration of inner ear hair cells to restore hearing loss is challenging. ATOH1 is a key gene in the development and regeneration of hair cells. Small activating RNAs (saRNAs) can target a gene to specifically upregulate its expression. This study aimed to explore whether small activating RNAs could induce the differentiation of human adipose-derived mesenchymal stem cells into hair cell-like cells with a combination of growth factors in vitro and thus provide a new strategy for hair cell regeneration and the treatment of sensorineural hearing loss. Fifteen small activating RNAs targeting the human ATOH1 gene were designed and screened in 293 T and human adipose-derived mesenchymal stem cells, and 3 of these candidates were found to be capable of effectively and stably activating ATOH1 gene expression. The selected small activating RNAs were then transfected into hair cell progenitor cells, and hair cell markers were examined 10 days after transfection. After transfection of the selected small activating RNAs, the expression of the characteristic markers of inner ear hair cells, POU class 4 homeobox 3 (POU4F3) and myosin VIIA (MYO7A), was detected. Human adipose-derived mesenchymal stem cells have the potential to differentiate into human hair cell progenitor cells. In vitro, small activating RNAs were able to induce the differentiation of hair cell progenitor cells into hair cell-like cells. Therefore, RNA activation technology has the potential to provide a new strategy for the regeneration of hair cells.
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Affiliation(s)
- Yong-Li Zhang
- Department of Otolaryngology, Peking Union Medical College and Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, Beijing, China
| | - Moorim Kang
- Ractigen Therapeutics, Nantong, Jiangsu, China
| | | | - Meng-Yao Xie
- Department of Otolaryngology, Peking Union Medical College and Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, Beijing, China
| | - Ruo-Yan Xue
- Department of Otolaryngology, Peking Union Medical College and Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, Beijing, China
| | - Qi Tang
- Department of Otolaryngology, Peking Union Medical College and Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, Beijing, China
| | - Hua Yang
- Department of Otolaryngology, Peking Union Medical College and Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, Beijing, China
| | - Long-Cheng Li
- Ractigen Therapeutics, Nantong, Jiangsu, China.,Institute of Reproductive Medicine, School of Medicine, Nantong University, Nantong, Jiangsu, China
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36
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Quemener AM, Centomo ML, Sax SL, Panella R. Small Drugs, Huge Impact: The Extraordinary Impact of Antisense Oligonucleotides in Research and Drug Development. Molecules 2022; 27:536. [PMID: 35056851 PMCID: PMC8781596 DOI: 10.3390/molecules27020536] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 12/15/2021] [Accepted: 12/18/2021] [Indexed: 01/27/2023] Open
Abstract
Antisense oligonucleotides (ASOs) are an increasingly represented class of drugs. These small sequences of nucleotides are designed to precisely target other oligonucleotides, usually RNA species, and are modified to protect them from degradation by nucleases. Their specificity is due to their sequence, so it is possible to target any RNA sequence that is already known. These molecules are very versatile and adaptable given that their sequence and chemistry can be custom manufactured. Based on the chemistry being used, their activity may significantly change and their effects on cell function and phenotypes can differ dramatically. While some will cause the target RNA to decay, others will only bind to the target and act as a steric blocker. Their incredible versatility is the key to manipulating several aspects of nucleic acid function as well as their process, and alter the transcriptome profile of a specific cell type or tissue. For example, they can be used to modify splicing or mask specific sites on a target. The entire design rather than just the sequence is essential to ensuring the specificity of the ASO to its target. Thus, it is vitally important to ensure that the complete process of drug design and testing is taken into account. ASOs' adaptability is a considerable advantage, and over the past decades has allowed multiple new drugs to be approved. This, in turn, has had a significant and positive impact on patient lives. Given current challenges presented by the COVID-19 pandemic, it is necessary to find new therapeutic strategies that would complement the vaccination efforts being used across the globe. ASOs may be a very powerful tool that can be used to target the virus RNA and provide a therapeutic paradigm. The proof of the efficacy of ASOs as an anti-viral agent is long-standing, yet no molecule currently has FDA approval. The emergence and widespread use of RNA vaccines during this health crisis might provide an ideal opportunity to develop the first anti-viral ASOs on the market. In this review, we describe the story of ASOs, the different characteristics of their chemistry, and how their characteristics translate into research and as a clinical tool.
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Affiliation(s)
- Anais M. Quemener
- University Rennes, CNRS, IGDR (Institute of Genetics and Development of Rennes)-UMR 6290, F-35000 Rennes, France;
| | - Maria Laura Centomo
- Department of Oncology, University of Turin, 10124 Turin, Italy;
- Center for Genomic Medicine, Desert Research Institute, Reno, NV 89512, USA;
| | - Scott L. Sax
- Center for Genomic Medicine, Desert Research Institute, Reno, NV 89512, USA;
| | - Riccardo Panella
- Center for Genomic Medicine, Desert Research Institute, Reno, NV 89512, USA;
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Hashimoto A, Sarker D, Reebye V, Jarvis S, Sodergren MH, Kossenkov A, Sanseviero E, Raulf N, Vasara J, Andrikakou P, Meyer T, Huang KW, Plummer R, Chee CE, Spalding D, Pai M, Khan S, Pinato DJ, Sharma R, Basu B, Palmer D, Ma YT, Evans J, Habib R, Martirosyan A, Elasri N, Reynaud A, Rossi JJ, Cobbold M, Habib NA, Gabrilovich DI. Upregulation of C/EBPα Inhibits Suppressive Activity of Myeloid Cells and Potentiates Antitumor Response in Mice and Patients with Cancer. Clin Cancer Res 2021; 27:5961-5978. [PMID: 34407972 PMCID: PMC8756351 DOI: 10.1158/1078-0432.ccr-21-0986] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 06/21/2021] [Accepted: 08/16/2021] [Indexed: 01/09/2023]
Abstract
PURPOSE To evaluate the mechanisms of how therapeutic upregulation of the transcription factor, CCAAT/enhancer-binding protein alpha (C/EBPα), prevents tumor progression in patients with advanced hepatocellular carcinoma (HCC) and in different mouse tumor models. EXPERIMENTAL DESIGN We conducted a phase I trial in 36 patients with HCC (NCT02716012) who received sorafenib as part of their standard care, and were given therapeutic C/EBPα small activating RNA (saRNA; MTL-CEBPA) as either neoadjuvant or adjuvant treatment. In the preclinical setting, the effects of MTL-CEBPA were assessed in several mouse models, including BNL-1ME liver cancer, Lewis lung carcinoma (LLC), and colon adenocarcinoma (MC38). RESULTS MTL-CEBPA treatment caused radiologic regression of tumors in 26.7% of HCC patients with an underlying viral etiology with 3 complete responders. MTL-CEBPA treatment in those patients caused a marked decrease in peripheral blood monocytic myeloid-derived suppressor cell (M-MDSC) numbers and an overall reduction in the numbers of protumoral M2 tumor-associated macrophages (TAM). Gene and protein analysis of patient leukocytes following treatment showed CEBPA activation affected regulation of factors involved in immune-suppressive activity. To corroborate this observation, treatment of all the mouse tumor models with MTL-CEBPA led to a reversal in the suppressive activity of M-MDSCs and TAMs, but not polymorphonuclear MDSCs (PMN-MDSC). The antitumor effects of MTL-CEBPA in these tumor models showed dependency on T cells. This was accentuated when MTL-CEBPA was combined with checkpoint inhibitors or with PMN-MDSC-targeted immunotherapy. CONCLUSIONS This report demonstrates that therapeutic upregulation of the transcription factor C/EBPα causes inactivation of immune-suppressive myeloid cells with potent antitumor responses across different tumor models and in cancer patients. MTL-CEBPA is currently being investigated in combination with pembrolizumab in a phase I/Ib multicenter clinical study (NCT04105335).
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Affiliation(s)
- Ayumi Hashimoto
- Wistar Institute, Philadelphia, Pennsylvania
- AstraZeneca, Gaithersburg, Maryland
| | | | - Vikash Reebye
- Imperial College London, London, UK.
- MiNA Therapeutics Ltd, London, UK
| | | | | | | | | | | | | | | | - Tim Meyer
- University College London Cancer Institute, London, UK
| | | | - Ruth Plummer
- Northern Centre for Cancer Care and Newcastle University, Newcastle upon Tyne, UK
| | - Cheng E Chee
- National University Cancer Institute Singapore, Singapore
| | | | | | | | | | | | | | - Daniel Palmer
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool and Clatterbridge Cancer Centre, Liverpool, UK
| | - Yuk-Ting Ma
- University of Birmingham and University Hospitals Birmingham NHS Trust, Birmingham, UK
| | - Jeff Evans
- University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, UK
| | | | | | | | | | - John J Rossi
- Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, Duarte, California
| | | | - Nagy A Habib
- Imperial College London, London, UK.
- MiNA Therapeutics Ltd, London, UK
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38
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Wei L, Chen J, Song C, Zhang Y, Zhang Y, Xu M, Feng C, Gao Y, Qian F, Wang Q, Shang D, Zhou X, Zhu J, Wang X, Jia Y, Liu J, Zhu Y, Li C. Cancer CRC: A Comprehensive Cancer Core Transcriptional Regulatory Circuit Resource and Analysis Platform. Front Oncol 2021; 11:761700. [PMID: 34712617 PMCID: PMC8546348 DOI: 10.3389/fonc.2021.761700] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 09/24/2021] [Indexed: 11/30/2022] Open
Abstract
A core transcriptional regulatory circuit (CRC) is a group of interconnected auto-regulating transcription factors (TFs) that form loops and can be identified by super-enhancers (SEs). Studies have indicated that CRCs play an important role in defining cellular identity and determining cellular fate. Additionally, core TFs in CRCs are regulators of cell-type-specific transcriptional regulation. However, a global view of CRC properties across various cancer types has not been generated. Thus, we integrated paired cancer ATAC-seq and H3K27ac ChIP-seq data for specific cell lines to develop the Cancer CRC (http://bio.liclab.net/Cancer_crc/index.html). This platform documented 94,108 cancer CRCs, including 325 core TFs. The cancer CRC also provided the “SE active core TFs analysis” and “TF enrichment analysis” tools to identify potentially key TFs in cancer. In addition, we performed a comprehensive analysis of core TFs in various cancer types to reveal conserved and cancer-specific TFs.
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Affiliation(s)
- Ling Wei
- School of Medical Informatics, Daqing Campus, Harbin Medical University, Daqing, China.,The First Affiliated Hospital, Institute of Cardiovascular Disease, Hengyang Medical School, University of South China, Hengyang, China.,Cardiovascular Lab of Big Data and Imaging Artificial Intelligence, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China
| | - Jiaxin Chen
- School of Medical Informatics, Daqing Campus, Harbin Medical University, Daqing, China
| | - Chao Song
- School of Medical Informatics, Daqing Campus, Harbin Medical University, Daqing, China.,The First Affiliated Hospital, Institute of Cardiovascular Disease, Hengyang Medical School, University of South China, Hengyang, China.,Cardiovascular Lab of Big Data and Imaging Artificial Intelligence, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China
| | - Yuexin Zhang
- School of Medical Informatics, Daqing Campus, Harbin Medical University, Daqing, China
| | - Yimeng Zhang
- School of Medical Informatics, Daqing Campus, Harbin Medical University, Daqing, China
| | - Mingcong Xu
- School of Medical Informatics, Daqing Campus, Harbin Medical University, Daqing, China
| | - Chenchen Feng
- School of Medical Informatics, Daqing Campus, Harbin Medical University, Daqing, China
| | - Yu Gao
- School of Medical Informatics, Daqing Campus, Harbin Medical University, Daqing, China
| | - Fengcui Qian
- School of Medical Informatics, Daqing Campus, Harbin Medical University, Daqing, China.,The First Affiliated Hospital, Institute of Cardiovascular Disease, Hengyang Medical School, University of South China, Hengyang, China.,Cardiovascular Lab of Big Data and Imaging Artificial Intelligence, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China
| | - Qiuyu Wang
- School of Medical Informatics, Daqing Campus, Harbin Medical University, Daqing, China.,The First Affiliated Hospital, Institute of Cardiovascular Disease, Hengyang Medical School, University of South China, Hengyang, China.,Cardiovascular Lab of Big Data and Imaging Artificial Intelligence, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China.,School of Computer, University of South China, Hengyang, China.,Hunan Provincial Base for Scientific and Technological Innovation Cooperation, University of South China, Hengyang, China
| | - Desi Shang
- The First Affiliated Hospital, Institute of Cardiovascular Disease, Hengyang Medical School, University of South China, Hengyang, China.,Cardiovascular Lab of Big Data and Imaging Artificial Intelligence, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China.,School of Computer, University of South China, Hengyang, China.,Hunan Provincial Base for Scientific and Technological Innovation Cooperation, University of South China, Hengyang, China
| | - Xinyuan Zhou
- School of Medical Informatics, Daqing Campus, Harbin Medical University, Daqing, China
| | - Jiang Zhu
- School of Medical Informatics, Daqing Campus, Harbin Medical University, Daqing, China
| | - Xiaopeng Wang
- School of Medical Informatics, Daqing Campus, Harbin Medical University, Daqing, China
| | - Yijie Jia
- School of Medical Informatics, Daqing Campus, Harbin Medical University, Daqing, China
| | - Jiaqi Liu
- The First Affiliated Hospital, Institute of Cardiovascular Disease, Hengyang Medical School, University of South China, Hengyang, China.,Cardiovascular Lab of Big Data and Imaging Artificial Intelligence, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China.,School of Computer, University of South China, Hengyang, China.,Hunan Provincial Base for Scientific and Technological Innovation Cooperation, University of South China, Hengyang, China
| | - Yanbing Zhu
- Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Beijing Clinical Research Institute, Beijing, China
| | - Chunquan Li
- The First Affiliated Hospital, Institute of Cardiovascular Disease, Hengyang Medical School, University of South China, Hengyang, China.,School of Medical Informatics, Daqing Campus, Harbin Medical University, Daqing, China.,Cardiovascular Lab of Big Data and Imaging Artificial Intelligence, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China.,School of Computer, University of South China, Hengyang, China.,Hunan Provincial Base for Scientific and Technological Innovation Cooperation, University of South China, Hengyang, China.,General Surgery Department, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin, China
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39
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Tan CP, Sinigaglia L, Gomez V, Nicholls J, Habib NA. RNA Activation-A Novel Approach to Therapeutically Upregulate Gene Transcription. Molecules 2021; 26:molecules26216530. [PMID: 34770939 PMCID: PMC8586927 DOI: 10.3390/molecules26216530] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 10/23/2021] [Accepted: 10/26/2021] [Indexed: 12/12/2022] Open
Abstract
RNA activation (RNAa) is a mechanism whereby RNA oligos complementary to genomic sequences around the promoter region of genes increase the transcription output of their target gene. Small activating RNA (saRNA) mediate RNAa through interaction with protein co-factors to facilitate RNA polymerase II activity and nucleosome remodeling. As saRNA are small, versatile and safe, they represent a new class of therapeutics that can rescue the downregulation of critical genes in disease settings. This review highlights our current understanding of saRNA biology and describes various examples of how saRNA are successfully used to treat various oncological, neurological and monogenic diseases. MTL-CEBPA, a first-in-class compound that reverses CEBPA downregulation in oncogenic processes using CEBPA-51 saRNA has entered clinical trial for the treatment of hepatocellular carcinoma (HCC). Preclinical models demonstrate that MTL-CEBPA reverses the immunosuppressive effects of myeloid cells and allows for the synergistic enhancement of other anticancer drugs. Encouraging results led to the initiation of a clinical trial combining MTL-CEBPA with a PD-1 inhibitor for treatment of solid tumors.
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Affiliation(s)
- Choon Ping Tan
- MiNA Therapeutics Ltd., Translation & Innovation Hub, 84 Wood Lane, London W12 0BZ, UK; (C.P.T.); (L.S.); (V.G.); (J.N.)
| | - Laura Sinigaglia
- MiNA Therapeutics Ltd., Translation & Innovation Hub, 84 Wood Lane, London W12 0BZ, UK; (C.P.T.); (L.S.); (V.G.); (J.N.)
| | - Valentí Gomez
- MiNA Therapeutics Ltd., Translation & Innovation Hub, 84 Wood Lane, London W12 0BZ, UK; (C.P.T.); (L.S.); (V.G.); (J.N.)
| | - Joanna Nicholls
- MiNA Therapeutics Ltd., Translation & Innovation Hub, 84 Wood Lane, London W12 0BZ, UK; (C.P.T.); (L.S.); (V.G.); (J.N.)
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London W12 0NN, UK
| | - Nagy A. Habib
- MiNA Therapeutics Ltd., Translation & Innovation Hub, 84 Wood Lane, London W12 0BZ, UK; (C.P.T.); (L.S.); (V.G.); (J.N.)
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London W12 0NN, UK
- Correspondence: ; Tel.: +44-(0)20-3313-8574
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40
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Yamada Y. Nucleic Acid Drugs-Current Status, Issues, and Expectations for Exosomes. Cancers (Basel) 2021; 13:cancers13195002. [PMID: 34638486 PMCID: PMC8508492 DOI: 10.3390/cancers13195002] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Revised: 09/28/2021] [Accepted: 10/01/2021] [Indexed: 12/16/2022] Open
Abstract
Simple Summary Nucleic acid drugs provide novel therapeutic modalities with characteristics that differ from those of small molecules and antibodies. In this review, I focus on the various mechanisms through which nucleic acid drugs act on, the status of their clinical development, and discuss several hurdles that need to be surmounted. In addition, by listing examples of how the progress in exosome biology can lead to the solution of problems in nucleic acid drug therapy, I hope that many more nucleic acid drugs including anticancer drugs will be developed in the future. Abstract Nucleic acid drugs are being developed as novel therapeutic modalities. They have great potential to treat human diseases such as cancers, viral infections, and genetic disorders due to unique characteristics that make it possible to approach undruggable targets using classical small molecule or protein/antibody-based biologics. In this review, I describe the advantages, classification, and clinical status of nucleic acid therapeutics. To date, more than 10 products have been launched, and many products have been tested in clinics. To promote the use of nucleic acid therapeutics such as antibodies, several hurdles need to be surmounted. The most important issue is the delivery of nucleic acids and several other challenges have been reported. Recent advanced delivery platforms are lipid nanoparticles and ligand conjugation approaches. With the progress of exosome biology, exosomes are expected to contribute to the solution of various problems associated with nucleic acid drugs.
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Affiliation(s)
- Yoji Yamada
- Research Management Office, Research Unit, R&D Division, Kyowa Kirin Co. Ltd., 1-9-2, Otemachi, Chiyoda-ku, Tokyo 100-0004, Japan
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41
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Meng L, Xu KX, Zhao MX, Li K, Zhu K, Yuan DW, Wang HN, Dai PG, Yan R. Nucleolar protein 6 promotes cell proliferation and acts as a potential novel prognostic marker for hepatocellular carcinoma. Chin Med J (Engl) 2021; 134:2611-2618. [PMID: 34561331 PMCID: PMC8577660 DOI: 10.1097/cm9.0000000000001655] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Background: Nucleolar protein 6 (NOL6) is a nucleolar RNA-associated protein that is highly conserved between species. It has been proved to be associated with the prognosis of liver cancer. However, the underlying mechanism has not been fully established. This study aimed to assess the relationship between NOL6 and liver cancer prognosis. Methods: We constructed an NOL6-short hairpin RNA (shRNA)-expressing lentivirus. Through viral transfection, cell growth assay and fluorescence-activated cell sorting, we evaluated the effect of shRNA-mediated NOL6 knockdown on the proliferation, colony formation, and apoptosis of hepatocellular carcinoma (HCC) cells. The relationship between NOL6 expression and HCC patient survival has been established through bioinformatics analysis. We also explored the downstream molecular regulatory network of NOL6 in HCC by performing an Ingenuity Pathway Analysis in the database. Results: Increased NOL6 expression was detected in HCC cells compared to normal controls; HCC patients with high NOL6 expression had poorer prognoses than those with low expression. NOL6 knockdown inhibited HCC cell proliferation, apoptosis, and colony formation. Also, MAPK8, CEBPA, and FOSL1 were selected as potential downstream genes of NOL6. Conclusions: NOL6 up-regulates HCC cell proliferation and affects downstream expression of related genes. Moreover, NOL6 is considered to be associated with poor prognosis in HCC patients.
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Affiliation(s)
- Lei Meng
- National Engineering Research Center for Miniaturized Detection Systems, The College of Life Sciences, Northwest University, Xi'an, Shaanxi 710069, China.,Department of Surgical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Kai-Xuan Xu
- National Engineering Research Center for Miniaturized Detection Systems, The College of Life Sciences, Northwest University, Xi'an, Shaanxi 710069, China
| | - Ming-Xi Zhao
- National Engineering Research Center for Miniaturized Detection Systems, The College of Life Sciences, Northwest University, Xi'an, Shaanxi 710069, China
| | - Kang Li
- Department of Surgical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Kun Zhu
- Department of Surgical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Da-Wei Yuan
- Department of Surgical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Hao-Nan Wang
- Department of Surgical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Peng-Gao Dai
- National Engineering Research Center for Miniaturized Detection Systems, The College of Life Sciences, Northwest University, Xi'an, Shaanxi 710069, China
| | - Rong Yan
- Department of Surgical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
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42
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Huang KW, Tan CP, Reebye V, Chee CE, Zacharoulis D, Habib R, Blakey DC, Rossi JJ, Habib N, Sodergren MH. MTL-CEBPA Combined with Immunotherapy or RFA Enhances Immunological Anti-Tumor Response in Preclinical Models. Int J Mol Sci 2021; 22:9168. [PMID: 34502076 PMCID: PMC8431011 DOI: 10.3390/ijms22179168] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 08/22/2021] [Accepted: 08/23/2021] [Indexed: 01/16/2023] Open
Abstract
The transcription factor CEBPA is a master regulator of liver homeostasis, myeloid cell differentiation and is downregulated in several oncogenic diseases. MTL-CEBPA is a small activating RNA drug which upregulates gene expression of CEBPA for treatment of hepatocellular carcinoma (HCC). We investigate whether MTL-CEBPA has immune modulatory effects by combining MTL-CEBPA with an anti-PD-1 checkpoint inhibitor (CPI) and/or radiofrequency ablation (RFA) in two preclinical models. First, mice with two flanks of HCC tumors (BNL) were treated with combinations of RFA (right flank), anti-PD-1 or MTL-CEBPA. The reduction of the left flank tumors was most pronounced in the group treated with RFA+anti-PD1+MTL-CEBPA and 7/8 animals responded. This was the only group with a significant increase in CD8+ and CD49b+/CD45+ tumor infiltrating lymphocytes (TIL). Second, a combination of anti-PD-1+MTL-CEBPA was tested in a CT26 colon cancer model and this treatment significantly reduced tumor size, modulated the tumor immune microenvironment and increased TILs. These data suggest a clinical role for combination treatment with CPIs, RFA and MTL-CEBPA through synergistic priming of the immune tumor response, enabling RFA and CPIs to have a pronounced anti-tumor effect including activity in non-treated tumors in the case of RFA.
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Affiliation(s)
- Kai-Wen Huang
- Hepatitis Research Center, Department of Surgery, National Taiwan University Hospital, College of Medicine, Taipei 100, Taiwan
- Centre of Mini-Invasive Interventional Oncology, National Taiwan University Hospital, Taipei 100, Taiwan
| | - Choon Ping Tan
- MiNA Therapeutics Ltd., London W12 0BZ, UK; (C.P.T.); (V.R.); (R.H.); (D.C.B.)
| | - Vikash Reebye
- MiNA Therapeutics Ltd., London W12 0BZ, UK; (C.P.T.); (V.R.); (R.H.); (D.C.B.)
- Department of Surgery and Cancer, Imperial College London, London W12 0NN, UK;
| | - Cheng Ean Chee
- Department of Haemato-Oncology, National University Cancer Institute, Singapore 119077, Singapore;
| | - Dimitris Zacharoulis
- Department of General Surgery, University Hospital of Larissa, 41110 Larissa, Greece;
| | - Robert Habib
- MiNA Therapeutics Ltd., London W12 0BZ, UK; (C.P.T.); (V.R.); (R.H.); (D.C.B.)
| | - David C. Blakey
- MiNA Therapeutics Ltd., London W12 0BZ, UK; (C.P.T.); (V.R.); (R.H.); (D.C.B.)
| | - John J. Rossi
- Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA;
| | - Nagy Habib
- MiNA Therapeutics Ltd., London W12 0BZ, UK; (C.P.T.); (V.R.); (R.H.); (D.C.B.)
- Department of Surgery and Cancer, Imperial College London, London W12 0NN, UK;
| | - Mikael H. Sodergren
- Department of Surgery and Cancer, Imperial College London, London W12 0NN, UK;
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43
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Yu AM, Tu MJ. Deliver the promise: RNAs as a new class of molecular entities for therapy and vaccination. Pharmacol Ther 2021; 230:107967. [PMID: 34403681 PMCID: PMC9477512 DOI: 10.1016/j.pharmthera.2021.107967] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 07/06/2021] [Accepted: 07/13/2021] [Indexed: 12/19/2022]
Abstract
The concepts of developing RNAs as new molecular entities for therapies have arisen again and again since the discoveries of antisense RNAs, direct RNA-protein interactions, functional noncoding RNAs, and RNA-directed gene editing. The feasibility was demonstrated with the development and utilization of synthetic RNA agents to selectively control target gene expression, modulate protein functions or alter the genome to manage diseases. Rather, RNAs are labile to degradation and cannot cross cell membrane barriers, making it hard to develop RNA medications. With the development of viable RNA technologies, such as chemistry and pharmaceutics, eight antisense oligonucleotides (ASOs) (fomivirsen, mipomersen, eteplirsen, nusinersen, inotersen, golodirsen, viltolarsen and casimersen), one aptamer (pegaptanib), and three small interfering RNAs (siRNAs) (patisiran, givosiran and lumasiran) have been approved by the United States Food and Drug Administration (FDA) for therapies, and two mRNA vaccines (BNT162b2 and mRNA-1273) under Emergency Use Authorization for the prevention of COVID-19. Therefore, RNAs have become a great addition to small molecules, proteins/antibodies, and cell-based modalities to improve the public health. In this article, we first summarize the general characteristics of therapeutic RNA agents, including chemistry, common delivery strategies, mechanisms of actions, and safety. By overviewing individual RNA medications and vaccines approved by the FDA and some agents under development, we illustrate the unique compositions and pharmacological actions of RNA products. A new era of RNA research and development will likely lead to commercialization of more RNA agents for medical use, expanding the range of therapeutic targets and increasing the diversity of molecular modalities.
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Affiliation(s)
- Ai-Ming Yu
- Department of Biochemistry and Molecular Medicine, UC Davis School of Medicine, Sacramento, CA 95817, USA.
| | - Mei-Juan Tu
- Department of Biochemistry and Molecular Medicine, UC Davis School of Medicine, Sacramento, CA 95817, USA
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44
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Chowdhury MMH, Salazar CJJ, Nurunnabi M. Recent advances in bionanomaterials for liver cancer diagnosis and treatment. Biomater Sci 2021; 9:4821-4842. [PMID: 34032223 DOI: 10.1039/d1bm00167a] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
According to the World Health Organization, liver cancer is the fourth leading cause of cancer associated with death worldwide. It demands effective treatment and diagnostic strategies to hinder its recurrence, complexities, aggressive metastasis and late diagnosis. With recent progress in nanotechnology, several nanoparticle-based diagnostic and therapeutic modalities have entered into clinical trials. With further developments in nanoparticle mediated liver cancer diagnosis and treatment, the approach holds promise for improved clinical liver cancer management. In this review, we discuss the key advances in nanoparticles that have potential for liver cancer diagnosis and treatment. We also discuss the potential of nanoparticles to overcome the limitations of existing therapeutic modalities.
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Affiliation(s)
- Mohammed Mehadi Hassan Chowdhury
- School of Medicine, Faculty of Health, Deakin University, 75 Pigdons Road, Waurnponds, Vic-3216, Australia and Department of Microbiology, Noakhali Science and Technology University, Noakhali-3814, Bangladesh
| | | | - Md Nurunnabi
- Environmental Science & Engineering, University of Texas at El Paso, TX 79968, USA. and Biomedical Engineering, University of Texas at El Paso, TX 79968, USA and Department of Pharmaceutical Sciences, School of Pharmacy, University of Texas at El Paso, TX 79902, USA and Border Biomedical Research Center, University of Texas at El Paso, TX 79968, USA
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45
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Liu Z, Wang S, Tapeinos C, Torrieri G, Känkänen V, El-Sayed N, Python A, Hirvonen JT, Santos HA. Non-viral nanoparticles for RNA interference: Principles of design and practical guidelines. Adv Drug Deliv Rev 2021; 174:576-612. [PMID: 34019958 DOI: 10.1016/j.addr.2021.05.018] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 05/04/2021] [Accepted: 05/15/2021] [Indexed: 02/08/2023]
Abstract
Ribonucleic acid interference (RNAi) is an innovative treatment strategy for a myriad of indications. Non-viral synthetic nanoparticles (NPs) have drawn extensive attention as vectors for RNAi due to their potential advantages, including improved safety, high delivery efficiency and economic feasibility. However, the complex natural process of RNAi and the susceptible nature of oligonucleotides render the NPs subject to particular design principles and requirements for practical fabrication. Here, we summarize the requirements and obstacles for fabricating non-viral nano-vectors for efficient RNAi. To address the delivery challenges, we discuss practical guidelines for materials selection and NP synthesis in order to maximize RNA encapsulation efficiency and protection against degradation, and to facilitate the cytosolic release of oligonucleotides. The current status of clinical translation of RNAi-based therapies and further perspectives for reducing the potential side effects are also reviewed.
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46
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Dong X, Wang F, Liu C, Ling J, Jia X, Shen F, Yang N, Zhu S, Zhong L, Li Q. Single-cell analysis reveals the intra-tumor heterogeneity and identifies MLXIPL as a biomarker in the cellular trajectory of hepatocellular carcinoma. Cell Death Discov 2021; 7:14. [PMID: 33462196 PMCID: PMC7814056 DOI: 10.1038/s41420-021-00403-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 12/11/2020] [Accepted: 12/23/2020] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a globally prevailing cancer with a low 5-year survival rate. Little is known about its intricate gene expression profile. Single-cell RNA sequencing is an indispensable tool to explore the genetic characteristics of HCC at a more detailed level. In this study, we profiled the gene expression of single cells from human HCC tumor and para-tumor tissues using the Smart-seq 2 sequencing method. Based on differentially expressed genes, we identified heterogeneous subclones in HCC tissues, including five HCC and two hepatocyte subclones. We then carried out hub-gene co-network and functional annotations analysis followed pseudo-time analysis with regulated transcriptional factor co-networks to determine HCC cellular trajectory. We found that MLX interacting protein like (MLXIPL) was commonly upregulated in the single cells and tissues and associated with a poor survival rate in HCC. Mechanistically, MLXIPL activation is crucial for promoting cell proliferation and inhibits cell apoptosis by accelerating cell glycolysis. Taken together, our work identifies the heterogeneity of HCC subclones, and suggests MLXIPL might be a promising therapeutic target for HCC.
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Affiliation(s)
- Xiao Dong
- Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Fan Wang
- Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Chuan Liu
- Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Jing Ling
- Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Xuebing Jia
- Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Feifei Shen
- Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Ning Yang
- Department of Hepatic Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China
| | - Sibo Zhu
- Center for Pharmacogenomics, School of Life Sciences, Fudan University, Shanghai, 200438, China
| | - Lin Zhong
- Department of Hepatobiliary and General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Qi Li
- Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China.
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47
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Jiang W, Zhu D, Wang C, Zhu Y. Tumor suppressing effects of tristetraprolin and its small double-stranded RNAs in bladder cancer. Cancer Med 2021; 10:269-285. [PMID: 33259133 PMCID: PMC7826468 DOI: 10.1002/cam4.3622] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 10/20/2020] [Accepted: 10/25/2020] [Indexed: 12/23/2022] Open
Abstract
Bladder cancer (BCa) is a common malignant tumor of urinary system with few treatments, so more useful therapeutic targets are still needed. Antitumor effects of tristetraprolin (TTP) have been explored in many type tumors, but its roles in bladder cancer are still unknown until now. In this study, public expression profiles and tissue microarray analysis showed that TTP mRNA and protein levels decreased in BCa relative to the normal bladder tissue. To explore biological functions of TTP in BCa, 488 TTP target genes, which could be both suppressed and bound by TTP, were identified by comprehensively analyzing publicly available high-throughput data obtained from Gene Expression Omnibus (GEO). Gene enrichment analysis showed that these genes were enriched in pathways such as cell cycle, epithelial to mesenchymal transition (EMT), and Wnt signaling. Clustering analysis and gene set variation analysis indicated that patients with high expression of TTP target genes had poorer prognosis and stronger tumor proliferation ability relative to the BCa patients with low expression of TTP target genes. In vitro experiments validated that TTP could suppress proliferation, migration, and invasiveness of BCa cells. And TTP could suppress mRNA expression of cyclin-dependent kinase 1 (CDK1) in BCa cells by target its 3' UTR. Then, we identified a new small double-stranded RNA (dsRNA) named dsTTP-973 which could increase TTP expression in BCa cells, in vivo and in vitro experiments revealed that dsTTP-973 could suppress aggressiveness of BCa. In conclusion, TTP played a role of tumor suppressor gene in BCa like other tumors, and its dsRNA named dsTTP-973 could induce TTP expression in BCa and suppress aggressiveness of BCa. With the help of materials science, dsTTP-973 may become a potential treatment for BCa in the future.
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Affiliation(s)
- Wen Jiang
- Department of UrologyRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Dandan Zhu
- Department of UrologyRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Chenghe Wang
- Department of UrologyRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Yu Zhu
- Department of UrologyRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
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48
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Dammes N, Peer D. Paving the Road for RNA Therapeutics. Trends Pharmacol Sci 2020; 41:755-775. [PMID: 32893005 PMCID: PMC7470715 DOI: 10.1016/j.tips.2020.08.004] [Citation(s) in RCA: 144] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 08/06/2020] [Accepted: 08/06/2020] [Indexed: 12/12/2022]
Abstract
Therapeutic RNA molecules possess high potential for treating medical conditions if they can successfully reach the target cell upon administration. However, unmodified RNA molecules are rapidly degraded and cleared from the circulation. In addition, their large size and negative charge complicates their passing through the cell membrane. The difficulty of RNA therapy, therefore, lies in the efficient intracellular delivery of intact RNA molecules to the tissue of interest without inducing adverse effects. Here, we outline the recent developments in therapeutic RNA delivery and discuss the wide potential in manipulating the function of cells with RNAs. The focus is not only on the variety of delivery strategies but also on the versatile nature of RNA and its wide applicability. This wide applicability is especially interesting when considering the modular nature of nucleic acids. An optimal delivery vehicle, therefore, can facilitate numerous clinical applications of RNA.
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Affiliation(s)
- Niels Dammes
- Laboratory of Precision NanoMedicine, Tel Aviv University, Tel Aviv 69978, Israel,School of Molecular Cell Biology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel,Department of Materials Sciences and Engineering, Iby and Aladar Fleischman Faculty of Engineering, Tel Aviv University, Tel Aviv 69978, Israel,Center for Nanoscience and Nanotechnology, and Tel Aviv University, Tel Aviv 69978, Israel,Cancer Biology Research Center, Tel Aviv University, Tel Aviv 69978, Israel
| | - Dan Peer
- Laboratory of Precision NanoMedicine, Tel Aviv University, Tel Aviv 69978, Israel; School of Molecular Cell Biology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel; Department of Materials Sciences and Engineering, Iby and Aladar Fleischman Faculty of Engineering, Tel Aviv University, Tel Aviv 69978, Israel; Center for Nanoscience and Nanotechnology, and Tel Aviv University, Tel Aviv 69978, Israel; Cancer Biology Research Center, Tel Aviv University, Tel Aviv 69978, Israel.
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49
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Bai X, Su G, Zhai S. Recent Advances in Nanomedicine for the Diagnosis and Therapy of Liver Fibrosis. NANOMATERIALS (BASEL, SWITZERLAND) 2020; 10:E1945. [PMID: 33003520 PMCID: PMC7599596 DOI: 10.3390/nano10101945] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 09/26/2020] [Accepted: 09/27/2020] [Indexed: 12/11/2022]
Abstract
Liver fibrosis, a reversible pathological process of inflammation and fiber deposition caused by chronic liver injury and can cause severe health complications, including liver failure, liver cirrhosis, and liver cancer. Traditional diagnostic methods and drug-based therapy have several limitations, such as lack of precision and inadequate therapeutic efficiency. As a medical application of nanotechnology, nanomedicine exhibits great potential for liver fibrosis diagnosis and therapy. Nanomedicine enhances imaging contrast and improves tissue penetration and cellular internalization; it simultaneously achieves targeted drug delivery, combined therapy, as well as diagnosis and therapy (i.e., theranostics). In this review, recent designs and development efforts of nanomedicine systems for the diagnosis, therapy, and theranostics of liver fibrosis are introduced. Relative to traditional methods, these nanomedicine systems generally demonstrate significant improvement in liver fibrosis treatment. Perspectives and challenges related to these nanomedicine systems translated from laboratory to clinical use are also discussed.
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Affiliation(s)
- Xue Bai
- School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China;
- School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
| | - Gaoxing Su
- School of Pharmacy, Nantong University, Nantong 226001, China
| | - Shumei Zhai
- School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China;
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Abstract
Oligonucleotides can be used to modulate gene expression via a range of processes including RNAi, target degradation by RNase H-mediated cleavage, splicing modulation, non-coding RNA inhibition, gene activation and programmed gene editing. As such, these molecules have potential therapeutic applications for myriad indications, with several oligonucleotide drugs recently gaining approval. However, despite recent technological advances, achieving efficient oligonucleotide delivery, particularly to extrahepatic tissues, remains a major translational limitation. Here, we provide an overview of oligonucleotide-based drug platforms, focusing on key approaches - including chemical modification, bioconjugation and the use of nanocarriers - which aim to address the delivery challenge.
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