|
1
|
McLain A, Kowalczyk A, Baran-Rachwalska P, Sutera FM, Robertson LJ, Nielsen NS, Enghild JJ, Cobice D, Bonelli F, Barbaro V, Ferrari S, Patterson B, Moore L, Marshall J, Nesbit MA, Moore T. TGFBI R124H mutant allele silencing in granular corneal dystrophy type 2 using topical siRNA delivery. J Control Release 2025; 382:113681. [PMID: 40185334 DOI: 10.1016/j.jconrel.2025.113681] [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: 12/24/2024] [Revised: 03/17/2025] [Accepted: 03/31/2025] [Indexed: 04/07/2025]
Abstract
In recent years, success has been achieved in treating several eye conditions with oligonucleotide-based therapies. Herein, we outline the experimentation involved in progressing selection and development of a lead therapeutic siRNA for R124H mutation of TGFBI gene which causes Granular Corneal Dystrophy Type 2 (GCD2/Avellino CD). Firstly, a series of siRNA designs, generated by a gene walk across the R124H TGFBI mutation site, were tested and a lead siRNA identified. The lead siRNA was delivered into an immortalised human corneal epithelial cell line to assess on-target efficacy and off-target effects. The in vivo efficacy of the lead R124H TGFBI siRNA, complexed with Bio-Courier technology, silicon stabilized hybrid lipid nanoparticles (sshLNP), was assessed in a mouse model of GCD2 which expressed the human R124H TGFBI transgene. Following topical siRNA application for 5 consecutive days, expression of the R124H mutant TGFBI transgene was measured and shown to be reduced by 22.4 % (± 15.7 %, p < 0.05). We investigated gene expression in the mouse cornea and showed expression of murine Tgfbi was 20-fold lower than TGFBI in human cornea, and expression of the mutant TGFBI transgene was a further 3-fold lower. This estimated 60-fold lower mutant transgene expression may explain the low frequency of corneal deposits observed in this mouse model, limiting its usefulness to test whether siRNA silencing is capable of phenotypic improvement or regression of GCD2/Avellino corneal dystrophy. We assessed WT TGFBI silencing in human primary corneal epithelial cells (PCEC) derived from human corneal limbal biopsy material, which express TGFBI at a similar level to human corneal biopsy. We demonstrated that a single 100 nM siRNA treatment, delivered by the sshLNP to the primary human corneal epithelial cells, gave 26.6 % (± 6.6 %, p < 0.001) reduction in TGFBI mRNA and a 15.4 % (±10.5 %, p < 0.05 %) reduction in TGFBi protein after 48 h. In consideration of the mutant gene expression levels in existing models of GCD2 disease, an ex vivo model of mutation-expressing primary corneal epithelial cells generated from corneal limbal biopsies from GCD2 patients would be more suitable than existing transgenic mouse models for future pre-clinical work in the development of gene silencing therapies for corneal dystrophies.
Collapse
Affiliation(s)
- Andrew McLain
- Integrated Diagnostics Laboratory, Northland House, CDHT, Frederick Street, Ulster University, Belfast, UK
| | - Amanda Kowalczyk
- Integrated Diagnostics Laboratory, Northland House, CDHT, Frederick Street, Ulster University, Belfast, UK
| | | | | | - Louise J Robertson
- Integrated Diagnostics Laboratory, Northland House, CDHT, Frederick Street, Ulster University, Belfast, UK
| | - Nadia Sukusu Nielsen
- Department of Molecular Biology and Genetics, Aarhus University, DK-8000 Aarhus C, Denmark
| | - Jan J Enghild
- Department of Molecular Biology and Genetics, Aarhus University, DK-8000 Aarhus C, Denmark
| | - Diego Cobice
- Integrated Diagnostics Laboratory, Northland House, CDHT, Frederick Street, Ulster University, Belfast, UK
| | - Filippo Bonelli
- Fondazione Banca degli Occhi del Veneto, Via Paccagnella 11, 30174 Venice, Italy
| | - Vanessa Barbaro
- Fondazione Banca degli Occhi del Veneto, Via Paccagnella 11, 30174 Venice, Italy
| | - Stefano Ferrari
- Fondazione Banca degli Occhi del Veneto, Via Paccagnella 11, 30174 Venice, Italy
| | - Benjamin Patterson
- Integrated Diagnostics Laboratory, Northland House, CDHT, Frederick Street, Ulster University, Belfast, UK
| | - Luca Moore
- LM Lassi Ltd, 22 Great Victoria Street, Belfast, Northern Ireland BT2 7BA, UK; University of York, Heslington, York YO10 5DD, UK
| | - John Marshall
- University College London, Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK
| | - M Andrew Nesbit
- Integrated Diagnostics Laboratory, Northland House, CDHT, Frederick Street, Ulster University, Belfast, UK
| | - Tara Moore
- Integrated Diagnostics Laboratory, Northland House, CDHT, Frederick Street, Ulster University, Belfast, UK; LM Lassi Ltd, 22 Great Victoria Street, Belfast, Northern Ireland BT2 7BA, UK; Avellino USA, Menlo Park, 4300 Bohannon Drive, Menlo Park, CA 94025, USA.
| |
Collapse
|
|
2
|
Ghasemiyeh P, Mohammadi-Samani S. siRNA-based delivery systems: Technologies, carriers, applications, and approved products. Eur J Pharmacol 2025; 996:177441. [PMID: 40023357 DOI: 10.1016/j.ejphar.2025.177441] [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: 12/25/2024] [Revised: 02/22/2025] [Accepted: 02/26/2025] [Indexed: 03/04/2025]
Abstract
Ribonucleic acid (RNA) therapeutics are a novel category of therapeutic agents that use different types of RNAs to regulate genes and modulate protein synthesis to treat a wide range of diseases. The main advantages of RNA therapeutics over conventional small molecule drugs would be the potential to target undruggable sites, ease of production and faster development process, and longer duration of action. Various types of RNA therapeutics including antisense oligonucleotides (ASO), RNA interference (RNAi), small interfering RNA (siRNA), microRNA (miRNA), and messenger RNA (mRNA), have been developed and used for various clinical applications, especially for gene and vaccine delivery purposes. This review is focused on various therapeutic applications of RNA-based delivery systems and then siRNA technologies are discussed in more detail. Next, the FDA-approved siRNA therapeutics and those are in clinical trials are listed and summarized. Then, various viral and non-viral vectors used for RNA delivery purposes are discussed. Finally, clinical applications of siRNA therapeutics are reviewed in detail.
Collapse
Affiliation(s)
- Parisa Ghasemiyeh
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Soliman Mohammadi-Samani
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Pharmaceutics, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
| |
Collapse
|
|
3
|
Campos-Parra AD, Sánchez-Marín D, Acevedo-Sánchez V. MicroRNAs as Sensitizers of Tyrosine Kinase Inhibitor Resistance in Cancer: Small Molecule Partnerships. Pharmaceuticals (Basel) 2025; 18:492. [PMID: 40283927 PMCID: PMC12030540 DOI: 10.3390/ph18040492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2025] [Revised: 03/25/2025] [Accepted: 03/26/2025] [Indexed: 04/29/2025] Open
Abstract
Tyrosine kinase inhibitors (TKIs) have revolutionized cancer treatments by being less toxic and improving the survival of cancer patients. The greatest challenge to their success is the resistance exhibited by cancer patients. However, the potential of microRNAs (miRNAs) for sensitizing molecules to TKIs has been well recognized, with several reports publishing promising results. Nonetheless, this therapeutic window faces challenges and several often-overlooked limitations. One of the most fundamental challenges is selecting the optimal miRNA candidates for clinical trials, as miRNAs are promiscuous and regulate hundreds of targets. In this review, we describe how miRNAs enhance sensitivity to TKIs across various types of cancer. We highlight several challenges and limitations in achieving a successful collaboration between small molecules (TKIs-miRNAs). Our focus is on proposing a workflow to select the most suitable miRNA candidate, recommending several available bioinformatics tools to develop a successful therapeutic partnership between TKIs and miRNAs. We hope that this initial proposal will provide valuable support for future research.
Collapse
Affiliation(s)
| | - David Sánchez-Marín
- Posgrado en Ciencias Biológicas, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Ciudad de México 04360, Mexico;
| | | |
Collapse
|
|
4
|
Yang Y, Yang C, Deng K, Xiao Y, Liu X, Du Z. Nucleic Acid Drugs in Radiotherapy. Chembiochem 2025; 26:e202400854. [PMID: 39903093 DOI: 10.1002/cbic.202400854] [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: 10/15/2024] [Revised: 02/01/2025] [Accepted: 02/03/2025] [Indexed: 02/06/2025]
Abstract
Radiotherapy remains a cornerstone of cancer treatment, using high-energy radiation to induce DNA damage in tumor cells, leading to cell death. However, its efficacy is often hindered by challenges such as radiation resistance and side effects. As a powerful class of functional molecules, nucleic acid drugs (NADs) present a promising solution to these limitations. Engineered to target key pathways like DNA repair and tumor hypoxia, NADs can enhance radiotherapy sensitivity. NADs can also serve as delivery vehicles for radiotherapy agents such as radionuclides, improving targeting accuracy and minimizing side effects. This review explores the role of NADs in optimizing radiotherapy, highlighting their mechanisms, clinical applications, and synergies with radiotherapy, ultimately offering a promising strategy for improving patient outcomes in cancer therapy.
Collapse
Affiliation(s)
- Yuying Yang
- College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, 310014, China
- The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China
| | - Cai Yang
- The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China
- Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan, 410082, China
| | - Kai Deng
- College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, 310014, China
- The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China
| | - Yating Xiao
- The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China
- School of Molecular Medicine, Hangzhou Institute for Advanced Study, Universities and Colleges Admissions Service (UCAS), Hangzhou, 310024, China
| | - Xiangsheng Liu
- The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China
| | - Zhen Du
- The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China
| |
Collapse
|
|
5
|
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.
Collapse
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.
| |
Collapse
|
|
6
|
Liu Y, Wang C, Fu X, Ren M. The Progress and Evolving Trends in Nucleic-Acid-Based Therapies. Biomolecules 2025; 15:376. [PMID: 40149911 PMCID: PMC11940734 DOI: 10.3390/biom15030376] [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: 12/23/2024] [Revised: 02/21/2025] [Accepted: 03/03/2025] [Indexed: 03/29/2025] Open
Abstract
Nucleic-acid-based therapies have emerged as a pivotal domain within contemporary biomedical science, marked by significant advancements in recent years. These innovative treatments primarily operate through the precise binding of DNA or RNA molecules to discrete target genes, subsequently suppressing the expression of the target proteins. The spectrum of nucleic-acid-based therapies encompasses antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), microRNAs (miRNAs), and messenger RNAs (mRNAs), etc. Compared to more traditional medicinal approaches, nucleic-acid-based therapies stand out for their highly targeted action on specific genes, as well as their potential for chemical modification to improve resistance to nucleases, ensuring sustained therapeutic activity and mitigating immunogenicity concerns. Nevertheless, these molecules' limited cellular permeability necessitates the deployment of delivery vectors to enhance their intracellular uptake and stability. As nucleic-acid-based therapies progressively display promising pharmacodynamic profiles, there has been a burgeoning interest in these treatments for applications in clinical research. This review aims to summarize the variety of nucleic acid drugs and their mechanisms, evaluate the present status in research and application, discourse on prospective trends, and potential challenges ahead. These innovative therapeutics are anticipated to assume a pivotal role in the management of a wide array of diseases.
Collapse
Affiliation(s)
| | | | - Xiuping Fu
- School of Chemistry and School of Life Sciences, Tiangong University, Tianjin 300387, China; (Y.L.); (C.W.)
| | - Mengtian Ren
- School of Chemistry and School of Life Sciences, Tiangong University, Tianjin 300387, China; (Y.L.); (C.W.)
| |
Collapse
|
|
7
|
Anwar AA, Jalan-Sakrikar N, Huebert RC. LncRNAs, RNA Therapeutics, and Emerging Technologies in Liver Pathobiology. Semin Liver Dis 2025; 45:1-14. [PMID: 39603269 DOI: 10.1055/a-2490-1921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2024]
Abstract
The field of ribonucleic acid (RNA) biology has revealed an array of noncoding RNA species, particularly long noncoding RNAs (lncRNAs), which play crucial roles in liver disease pathogenesis. This review explores the diverse functions of lncRNAs in liver pathology, including metabolic-associated steatotic liver disease, hepatocellular carcinoma, alcohol-related liver disease, and cholangiopathies such as primary sclerosing cholangitis and cholangiocarcinoma. We highlight key lncRNAs that regulate lipid metabolism, inflammation, fibrosis, and oncogenesis in the liver, demonstrating their diagnostic and therapeutic potential. Emerging RNA-based therapies, such as mRNA therapy, RNA interference, and antisense oligonucleotides, offer approaches to modulate lncRNA activity and address liver disease at a molecular level. Advances in sequencing technologies and bioinformatics pipelines are simultaneously enabling the identification and functional characterization of novel lncRNAs, driving innovation in personalized medicine. In conclusion, this review highlights the potential of lncRNAs as biomarkers and therapeutic targets in liver disease and emphasizes the need for further research into their regulatory mechanisms and clinical applications.
Collapse
Affiliation(s)
- Abid A Anwar
- Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, Minnesota
- Gastroenterology Research Unit, Mayo Clinic and Foundation, Rochester, Minnesota
| | - Nidhi Jalan-Sakrikar
- Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, Minnesota
- Gastroenterology Research Unit, Mayo Clinic and Foundation, Rochester, Minnesota
- Mayo Clinic Center for Cell Signaling in Gastroenterology, Mayo Clinic and Foundation, Rochester, Minnesota
| | - Robert C Huebert
- Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, Minnesota
- Gastroenterology Research Unit, Mayo Clinic and Foundation, Rochester, Minnesota
- Mayo Clinic Center for Cell Signaling in Gastroenterology, Mayo Clinic and Foundation, Rochester, Minnesota
| |
Collapse
|
|
8
|
Ramírez-Cortés F, Ménová P. Hepatocyte targeting via the asialoglycoprotein receptor. RSC Med Chem 2025; 16:525-544. [PMID: 39628900 PMCID: PMC11609720 DOI: 10.1039/d4md00652f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Accepted: 11/19/2024] [Indexed: 12/06/2024] Open
Abstract
This review highlights the potential of asialoglycoprotein receptor (ASGPR)-mediated targeting in advancing liver-specific treatments and underscores the ongoing progress in the field. First, we provide a comprehensive examination of the nature of ASGPR ligands, both natural and synthetic. Next, we explore various drug delivery strategies leveraging ASGPR, with a particular emphasis on the delivery of therapeutic nucleic acids such as small interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs). An in-depth analysis of the current status of RNA interference (RNAi) and ASO-based therapeutics is included, detailing approved therapies and those in various stages of clinical development (phases 1 to 3). Afterwards, we give an overview of other ASGPR-targeted conjugates, such as those with peptide nucleic acids or aptamers. Finally, targeted protein degradation of extracellular proteins through ASGPR is briefly discussed.
Collapse
Affiliation(s)
| | - Petra Ménová
- University of Chemistry and Technology, Prague Technická 5 16628 Prague 6 Czech Republic
| |
Collapse
|
|
9
|
Sergeeva OV, Luo L, Guiseppi-Elie A. Cancer theragnostics: closing the loop for advanced personalized cancer treatment through the platform integration of therapeutics and diagnostics. Front Bioeng Biotechnol 2025; 12:1499474. [PMID: 39898278 PMCID: PMC11782185 DOI: 10.3389/fbioe.2024.1499474] [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: 09/20/2024] [Accepted: 12/30/2024] [Indexed: 02/04/2025] Open
Abstract
Cancer continues to be one of the leading causes of death worldwide, and conventional cancer therapies such as chemotherapy, radiation therapy, and surgery have limitations. RNA therapy and cancer vaccines hold considerable promise as an alternative to conventional therapies for their ability to enable personalized therapy with improved efficacy and reduced side effects. The principal approach of cancer vaccines is to induce a specific immune response against cancer cells. However, a major challenge in cancer immunotherapy is to predict which patients will respond to treatment and to monitor the efficacy of the vaccine during treatment. Theragnostics, an integration of diagnostic and therapeutic capabilities into a single hybrid platform system, has the potential to address these challenges by enabling real-time monitoring of treatment response while allowing endogenously controlled personalized treatment adjustments. In this article, we review the current state-of-the-art in theragnostics for cancer vaccines and RNA therapy, including imaging agents, biomarkers, and other diagnostic tools relevant to cancer, and their application in cancer therapy development and personalization. We also discuss the opportunities and challenges for further development and clinical translation of theragnostics in cancer vaccines.
Collapse
Affiliation(s)
| | - Liang Luo
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Anthony Guiseppi-Elie
- Bioelectronics, Biosensors and Biochips (C3B), Department of Biomedical Engineering, Texas A&M University, College Station, TX, United States
- Department of Cardiovascular Sciences, Houston Methodist Institute for Academic Medicine and Full Affiliate Member, Houston Methodist Research Institute, Houston, TX, United States
- ABTECH Scientific, Inc., Biotechnology Research Park, Richmond, VA, United States
| |
Collapse
|
|
10
|
Daga P, Singh G, Menon T, Sztukowska M, Kalra DK. Emerging RNAi Therapies to Treat Hypertension. Mol Diagn Ther 2025; 29:25-41. [PMID: 39400663 DOI: 10.1007/s40291-024-00747-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/17/2024] [Indexed: 10/15/2024]
Abstract
Hypertension (HTN), often dubbed the "silent killer," poses a significant global health challenge, affecting over 1.3 billion individuals. Despite advances in treatment, effective long-term blood pressure (BP) control remains elusive, necessitating novel therapeutic approaches. Poor control of BP remains a leading cause of cardiovascular morbidity and mortality worldwide and is becoming an even larger global health problem due to the aging population, rising rates of obesity, poorer dietary patterns and overall cardiometabolic health, and suboptimal rates of patient adherence and optimal BP control. Ribonucleic acid interference (RNAi) technology, which leverages the body's natural gene-silencing mechanism, has emerged as a promising strategy for several diseases and has recently been tested for its antihypertensive effects. We systematically reviewed peer-reviewed articles from databases including PubMed, EMBASE, and Scopus for studies examining RNAi's role in managing HTN, focusing on mechanisms, clinical utility, and safety profile. Key early-phase trials of some RNAi-leading candidate drugs are detailed. Also highlighted are challenges such as target specificity, delivery mechanisms, durability of effect, and immunogenicity. We conclude by summarizing how RNAi has a significant potential role in HTN therapy due to their unique benefits, such as long-term duration of action, infrequent dosing, and lack of major side effects.
Collapse
Affiliation(s)
- Pawan Daga
- Department of Internal Medicine, University of Louisville School of Medicine, Louisville, KY, USA
| | - Gurnoor Singh
- Division of Cardiology, Department of Medicine, Rudd Heart and Lung Center, University of Louisville School of Medicine, 201 Abraham Flexner Way, Suite 600, Louisville, KY, 40202, USA
| | - Tushar Menon
- Division of Cardiology, Department of Medicine, Rudd Heart and Lung Center, University of Louisville School of Medicine, 201 Abraham Flexner Way, Suite 600, Louisville, KY, 40202, USA
| | - Maryta Sztukowska
- Clinical Trials Unit, University of Louisville School of Medicine, Louisville, KY, USA
- University of Information Technology and Management, Rzeszow, Poland
| | - Dinesh K Kalra
- Division of Cardiology, Department of Medicine, Rudd Heart and Lung Center, University of Louisville School of Medicine, 201 Abraham Flexner Way, Suite 600, Louisville, KY, 40202, USA.
| |
Collapse
|
|
11
|
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.
Collapse
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.
| |
Collapse
|
|
12
|
Kubisch I, Wohmann N, Wissniowski TT, Stauch T, Oettel L, Diehl-Wiesenecker E, Somasundaram R, Stölzel U. German Real-World Experience of Patients with Diverse Features of Acute Intermittent Porphyria Treated with Givosiran. J Clin Med 2024; 13:6779. [PMID: 39597922 PMCID: PMC11594983 DOI: 10.3390/jcm13226779] [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: 09/03/2024] [Revised: 10/28/2024] [Accepted: 10/29/2024] [Indexed: 11/29/2024] Open
Abstract
Background/Objectives: Acute intermittent porphyria (AIP) is a metabolic disease characterised by neurovisceral crises with episodes of acute abdominal pain alongside life-altering, and often hidden, chronic symptoms. The elimination of precipitating factors, hemin therapy, and pain relief are strategies used to treat porphyria symptoms, but are often reserved for patients suffering recurrent, acute attacks. Givosiran (siRNA) is an emerging AIP therapy capable of silencing delta-aminolevulinic acid synthase-1 (ALAS1) and, in turn, reducing the accumulation of delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) that precede porphyria symptoms. The aim of this study was to investigate the efficacy and safety of givosiran administration in patients with both acute and chronic AIP burden, who were poorly responsive to current therapies, using a personalised medicine approach. Methods: Real-world data were collected in consecutive patients treated with givosiran at an accredited German Porphyria Clinical Center. Biochemical, clinical, and HR-QoL outcomes were monitored alongside adverse events (AEs). Results: Twenty-eight patients treated between 2018 and 2024 were sub-categorised into groups corresponding to Ipnet terms 13 'Sporadic Attacks, 5 'Symptomatic High Excretors', 5 'Prophylactic Heme', and 5 "Recurrent Attacks'. The mean time from diagnosis to treatment was 9.2 years (range in months 1-324), and the mean duration of treatment was 30 months (range 3-68). After 6 months of monthly givosiran injection (2.5 mg/kg), all patients' ALA levels reached <2ULN, and 60% of patients attained PBG levels < 2ULN (p < 0.001). These biochemical responses were not different between sub-groups (p > 0.05). Clinically, 75% of patients' chronic and acute porphyria symptoms improved. The total patient populations' annualised attack ratio (AAR) improved; Historical AAR: 2.9 (0-12.0) vs. Givo AAR: 0.45 (0-3.0) (p < 0.01). During follow-up, nine patients experienced minor breakthrough episodes. Of these, three patients required hemin infusion. An association between clinical success and a shorter interim period between diagnosis and treatment was evident (r = -0.522, p = 0.0061). All patients' indices of HR-QoL improved under givosiran, including mental health (38%, p < 0.0001) and pain (38%, p < 0.0001). Patient-reported health (givosiran 77.9% vs. baseline 37.1%, p < 0.0001) and clinical outcome scores (86.9%: good-very good) were also positive. Two patients withdrew from treatment <6 months, citing fatigue, which was a common side effect. A mild elevation in liver enzymes (AST and/or ALT < 1.5ULN, 15.4%) and reduced glomerular filtration rates (GFR, 11.5%) were also evident, but no life-threatening adverse events (AEs) were attributed to givosiran treatment. Conclusions: Givosiran is effective in preventing severe acute attacks and reducing the chronic health burden in patients with acute intermittent porphyria. Importantly, HR-QoL improved in patients suffering chronic AIP burden with few incidences of historical attacks. All patients experienced substantially improved mental health, ease of living, and self-perceived health.
Collapse
Affiliation(s)
- Ilja Kubisch
- Porphyria Center, Chemnitz Hospital, 09116 Chemnitz, Germany; (I.K.); (N.W.); (T.T.W.); (L.O.)
| | - Nils Wohmann
- Porphyria Center, Chemnitz Hospital, 09116 Chemnitz, Germany; (I.K.); (N.W.); (T.T.W.); (L.O.)
| | | | | | - Lucienne Oettel
- Porphyria Center, Chemnitz Hospital, 09116 Chemnitz, Germany; (I.K.); (N.W.); (T.T.W.); (L.O.)
| | - Eva Diehl-Wiesenecker
- Department of Emergency Medicine and Porphyria Clinic, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10115 Berlin, Germany; (E.D.-W.); (R.S.)
| | - Rajan Somasundaram
- Department of Emergency Medicine and Porphyria Clinic, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10115 Berlin, Germany; (E.D.-W.); (R.S.)
| | - Ulrich Stölzel
- Porphyria Center, Chemnitz Hospital, 09116 Chemnitz, Germany; (I.K.); (N.W.); (T.T.W.); (L.O.)
| |
Collapse
|
|
13
|
Wei PS, Thota N, John G, Chang E, Lee S, Wang Y, Ma Z, Tsai YH, Mei KC. Enhancing RNA-lipid nanoparticle delivery: Organ- and cell-specificity and barcoding strategies. J Control Release 2024; 375:366-388. [PMID: 39179112 PMCID: PMC11972657 DOI: 10.1016/j.jconrel.2024.08.030] [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: 04/24/2024] [Revised: 07/25/2024] [Accepted: 08/19/2024] [Indexed: 08/26/2024]
Abstract
Recent advancements in RNA therapeutics highlight the critical need for precision gene delivery systems that target specific organs and cells. Lipid nanoparticles (LNPs) have emerged as key vectors in delivering mRNA and siRNA, offering protection against enzymatic degradation, enabling targeted delivery and cellular uptake, and facilitating RNA cargo release into the cytosol. This review discusses the development and optimization of organ- and cell-specific LNPs, focusing on their design, mechanisms of action, and therapeutic applications. We explore innovations such as DNA/RNA barcoding, which facilitates high-throughput screening and precise adjustments in formulations. We address major challenges, including improving endosomal escape, minimizing off-target effects, and enhancing delivery efficiencies. Notable clinical trials and recent FDA approvals illustrate the practical applications and future potential of LNP-based RNA therapies. Our findings suggest that while considerable progress has been made, continued research is essential to resolve existing limitations and bridge the gap between preclinical and clinical evaluation of the safety and efficacy of RNA therapeutics. This review highlights the dynamic progress in LNP research. It outlines a roadmap for future advancements in RNA-based precision medicine.
Collapse
Affiliation(s)
- Pu-Sheng Wei
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Binghamton, Johnson City, New York, NY 13790, USA
| | - Nagasri Thota
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Binghamton, Johnson City, New York, NY 13790, USA
| | - Greshma John
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Binghamton, Johnson City, New York, NY 13790, USA
| | - Evelyn Chang
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Binghamton, Johnson City, New York, NY 13790, USA
| | - Sunjae Lee
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Binghamton, Johnson City, New York, NY 13790, USA
| | - Yuanjun Wang
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Binghamton, Johnson City, New York, NY 13790, USA
| | - Zitao Ma
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Binghamton, Johnson City, New York, NY 13790, USA
| | - Yu-Hsuan Tsai
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Binghamton, Johnson City, New York, NY 13790, USA
| | - Kuo-Ching Mei
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Binghamton, Johnson City, New York, NY 13790, USA.
| |
Collapse
|
|
14
|
Miyaji K, Masaki Y, Seio K. Inhibitory Effects on RNA Binding and RNase H Induction Activity of Prodrug-Type Oligodeoxynucleotides Modified with a Galactosylated Self-Immolative Linker Cleavable by β-Galactosidase. Bioconjug Chem 2024. [PMID: 39376088 DOI: 10.1021/acs.bioconjchem.4c00376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/09/2024]
Abstract
Prodrug-type oligonucleotides (prodrug-ONs) are a class of oligonucleotide designed for activation under specific intracellular conditions or external stimuli. Prodrug-ONs can be activated in the target tissues or cells, thereby reducing the risk of adverse effects. In this study, we synthesized prodrug-type oligodeoxynucleotides activated by β-galactosidase, an enzyme that is overexpressed in cancer and senescent cells. These oligodeoxynucleotides (ODNs) contain a modified thymidine conjugated with galactose via a self-immolative linker at the O4-position. UV-melting analysis revealed that the modifications decreased the melting temperature (Tm) compared with that of the unmodified ODN when hybridized with complementary RNA. Furthermore, cleavage of the glycosidic bond by β-galactosidase resulted in the spontaneous removal of the linker from the nucleobase moiety, generating unmodified ODNs. Additionally, the introduction of multiple modified thymidines into ODNs completely inhibited the RNase H-mediated cleavage of complementary RNA. These findings suggest the possibility of developing prodrug-ONs, which are specifically activated in cancer cells or senescent cells with high β-galactosidase expression.
Collapse
Affiliation(s)
- Kento Miyaji
- Department of Life Science and Technology, Tokyo Institute of Technology, Midori-ku, Yokohama, Kanagawa 226-8501, Japan
| | - Yoshiaki Masaki
- Department of Life Science and Technology, Tokyo Institute of Technology, Midori-ku, Yokohama, Kanagawa 226-8501, Japan
- Nucleotide and Peptide Drug Discovery Center, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8519, Japan
| | - Kohji Seio
- Department of Life Science and Technology, Tokyo Institute of Technology, Midori-ku, Yokohama, Kanagawa 226-8501, Japan
| |
Collapse
|
|
15
|
Miao Y, Fu C, Yu Z, Yu L, Tang Y, Wei M. Current status and trends in small nucleic acid drug development: Leading the future. Acta Pharm Sin B 2024; 14:3802-3817. [PMID: 39309508 PMCID: PMC11413693 DOI: 10.1016/j.apsb.2024.05.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 03/15/2024] [Accepted: 04/12/2024] [Indexed: 09/25/2024] Open
Abstract
Small nucleic acid drugs, composed of nucleotides, represent a novel class of pharmaceuticals that differ significantly from conventional small molecule and antibody-based therapeutics. These agents function by selectively targeting specific genes or their corresponding messenger RNAs (mRNAs), further modulating gene expression and regulating translation-related processes. Prominent examples within this category include antisense oligonucleotides (ASO), small interfering RNAs (siRNAs), microRNAs (miRNAs), and aptamers. The emergence of small nucleic acid drugs as a focal point in contemporary biopharmaceutical research is attributed to their remarkable specificity, facile design, abbreviated development cycles, expansive target spectrum, and prolonged activity. Overcoming challenges such as poor stability, immunogenicity, and permeability issues have been addressed through the integration of chemical modifications and the development of drug delivery systems. This review provides an overview of the current status and prospective trends in small nucleic acid drug development. Commencing with a historical context, we introduce the primary classifications and mechanisms of small nucleic acid drugs. Subsequently, we delve into the advantages of the U.S. Food and Drug Administration (FDA) approved drugs and mainly discuss the challenges encountered during their development. Apart from researching chemical modification and delivery system that efficiently deliver and enrich small nucleic acid drugs to target tissues, promoting endosomal escape is a critical scientific question and important research direction in siRNA drug development. Future directions in this field will prioritize addressing these challenges to facilitate the clinical transformation of small nucleic acid drugs.
Collapse
Affiliation(s)
- Yuxi Miao
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang 110122, China
- Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang 110122, China
- Liaoning Medical Diagnosis and Treatment Center, Shenyang 110000, China
| | - Chen Fu
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang 110122, China
- Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang 110122, China
| | - Zhaojin Yu
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang 110122, China
- Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang 110122, China
| | - Lifeng Yu
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang 110122, China
| | - Yu Tang
- Department of Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang 110042, China
| | - Minjie Wei
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang 110122, China
- Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang 110122, China
- Liaoning Medical Diagnosis and Treatment Center, Shenyang 110000, China
| |
Collapse
|
|
16
|
Jin SE, Sung JH. Delivery Strategies of siRNA Therapeutics for Hair Loss Therapy. Int J Mol Sci 2024; 25:7612. [PMID: 39062852 PMCID: PMC11277092 DOI: 10.3390/ijms25147612] [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: 05/01/2024] [Revised: 06/25/2024] [Accepted: 07/01/2024] [Indexed: 07/28/2024] Open
Abstract
Therapeutic needs for hair loss are intended to find small interfering ribonucleic acid (siRNA) therapeutics for breakthrough. Since naked siRNA is restricted to meet a druggable target in clinic,, delivery systems are indispensable to overcome intrinsic and pathophysiological barriers, enhancing targetability and persistency to ensure safety, efficacy, and effectiveness. Diverse carriers repurposed from small molecules to siRNA can be systematically or locally employed in hair loss therapy, followed by the adoption of new compositions associated with structural and environmental modification. The siRNA delivery systems have been extensively studied via conjugation or nanoparticle formulation to improve their fate in vitro and in vivo. In this review, we introduce clinically tunable siRNA delivery systems for hair loss based on design principles, after analyzing clinical trials in hair loss and currently approved siRNA therapeutics. We further discuss a strategic research framework for optimized siRNA delivery in hair loss from the scientific perspective of clinical translation.
Collapse
Affiliation(s)
- Su-Eon Jin
- Epi Biotech Co., Ltd., Incheon 21984, Republic of Korea
| | | |
Collapse
|
|
17
|
Qiu Y, Wang C, Wang J, L. V. Q, Sun L, Yang Y, Liu M, Liu X, Li C, Tang B. Revealing the dynamic whole transcriptome landscape of Clonorchis sinensis: Insights into the regulatory roles of noncoding RNAs and microtubule-related genes in development. PLoS Negl Trop Dis 2024; 18:e0012311. [PMID: 38991028 PMCID: PMC11265684 DOI: 10.1371/journal.pntd.0012311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 07/23/2024] [Accepted: 06/23/2024] [Indexed: 07/13/2024] Open
Abstract
Clonorchis sinensis is a significant zoonotic food-borne parasite that causes a range of hepatobiliary diseases, which in severe cases can even lead to cholangiocarcinoma. To explore new diagnostic and treatment strategies, the dynamic RNA regulatory processes across different developmental stages of C. sinensis were analyzed by using whole-transcriptome sequencing. The chromosomal-level genome of C. sinensis was used for sequence alignment and annotation. In this study, we identified a total of 59,103 RNAs in the whole genome, including 2,384 miRNAs, 25,459 mRNAs, 27,564 lncRNAs and 3,696 circRNAs. Differential expression analysis identified 6,556 differentially expressed mRNAs, 2,231 lncRNAs, 877 miRNAs and 20 circRNAs at different developmental stages. Functional enrichment analysis highlighted the critical role of microtubule-related biological processes in the growth and development of C. sinensis. And coexpression analysis revealed 97 lncRNAs and 85 circRNAs that were coexpressed with 42 differentially expressed mRNAs that associated with microtubules at different developmental stages of C. sinensis. The expression of the microtubule-related genes dynein light chain 2 (DLC2) and dynein light chain 4 (DLC4) increased with C. sinensis development, and DLC2/4 could be inhibited by albendazole. Finally, by constructing competing endogenous RNA (ceRNA) networks, the lncRNA-miRNA-mRNA and circRNA-miRNA-mRNA regulatory relationships were constructed, and the ceRNA networks of MSTRG.14258.5-novel_miR_2287-newGene_28215 and MSTRG.14258.5-novel_miR_2216-CSKR_109340 were verified. This study suggests, through whole transcriptome sequencing, that the context of microtubule regulation may play an essential role in the development and growth of C. sinensis.
Collapse
Affiliation(s)
- Yangyuan Qiu
- 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, PR China
| | - Cunzhou Wang
- Jiashi County Hospital of Uygur Medicine, Kashgar City, Xinjiang Uygur Autonomous Region, PR China
| | - Jing Wang
- 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, PR China
| | - Qingbo L. V.
- 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, PR China
| | - Lulu Sun
- 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, PR China
| | - Yaming Yang
- Yunnan Institute of Parasitic Diseases, Pu’er, PR China
| | - Mingyuan Liu
- 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, PR China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, PR China
| | - Xiaolei Liu
- 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, PR China
| | - Chen Li
- 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, PR China
| | - Bin Tang
- 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, PR China
| |
Collapse
|
|
18
|
Saw PE, Song E. Advancements in clinical RNA therapeutics: Present developments and prospective outlooks. Cell Rep Med 2024; 5:101555. [PMID: 38744276 PMCID: PMC11148805 DOI: 10.1016/j.xcrm.2024.101555] [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: 01/16/2024] [Revised: 03/05/2024] [Accepted: 04/15/2024] [Indexed: 05/16/2024]
Abstract
RNA molecules have emerged as promising clinical therapeutics due to their ability to target "undruggable" proteins or molecules with high precision and minimal side effects. Nevertheless, the primary challenge in RNA therapeutics lies in rapid degradation and clearance from systemic circulation, the inability to traverse cell membranes, and the efficient intracellular delivery of bioactive RNA molecules. In this review, we explore the implications of RNAs in diseases and provide a chronological overview of the development of RNA therapeutics. Additionally, we summarize the technological advances in RNA-screening design, encompassing various RNA databases and design platforms. The paper then presents an update on FDA-approved RNA therapeutics and those currently undergoing clinical trials for various diseases, with a specific emphasis on RNA medicine and RNA vaccines.
Collapse
Affiliation(s)
- Phei Er Saw
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Nanhai Clinical Translational Center, Sun Yat-sen Memorial Hospital, Foshan 528200, China
| | - Erwei Song
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Nanhai Clinical Translational Center, Sun Yat-sen Memorial Hospital, Foshan 528200, China; Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China.
| |
Collapse
|
|
19
|
Baylot V, Le TK, Taïeb D, Rocchi P, Colleaux L. Between hope and reality: treatment of genetic diseases through nucleic acid-based drugs. Commun Biol 2024; 7:489. [PMID: 38653753 PMCID: PMC11039704 DOI: 10.1038/s42003-024-06121-9] [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: 08/22/2023] [Accepted: 03/28/2024] [Indexed: 04/25/2024] Open
Abstract
Rare diseases (RD) affect a small number of people compared to the general population and are mostly genetic in origin. The first clinical signs often appear at birth or in childhood, and patients endure high levels of pain and progressive loss of autonomy frequently associated with short life expectancy. Until recently, the low prevalence of RD and the gatekeeping delay in their diagnosis have long hampered research. The era of nucleic acid (NA)-based therapies has revolutionized the landscape of RD treatment and new hopes arise with the perspectives of disease-modifying drugs development as some NA-based therapies are now entering the clinical stage. Herein, we review NA-based drugs that were approved and are currently under investigation for the treatment of RD. We also discuss the recent structural improvements of NA-based therapeutics and delivery system, which overcome the main limitations in their market expansion and the current approaches that are developed to address the endosomal escape issue. We finally open the discussion on the ethical and societal issues that raise this new technology in terms of regulatory approval and sustainability of production.
Collapse
Affiliation(s)
- Virginie Baylot
- Aix Marseille Univ, CNRS, CINAM, ERL INSERM U 1326, CERIMED, Marseille, France.
| | - Thi Khanh Le
- Aix Marseille Univ, CNRS, CINAM, ERL INSERM U 1326, CERIMED, Marseille, France
| | - David Taïeb
- Aix Marseille Univ, CNRS, CINAM, ERL INSERM U 1326, CERIMED, Marseille, France
| | - Palma Rocchi
- Aix Marseille Univ, CNRS, CINAM, ERL INSERM U 1326, CERIMED, Marseille, France.
| | - Laurence Colleaux
- Aix Marseille Univ, CNRS, CINAM, ERL INSERM U 1326, CERIMED, Marseille, France
| |
Collapse
|
|
20
|
Ha Thi HT, Than VT. Recent applications of RNA therapeutic in clinics. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2024; 203:115-150. [PMID: 38359994 DOI: 10.1016/bs.pmbts.2023.12.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/17/2024]
Abstract
Ribonucleic acid (RNA) therapy has been extensively researched for several decades and has garnered significant attention in recent years owing to its potential in treating a broad spectrum of diseases. It falls under the domain of gene therapy, leveraging RNA molecules as a therapeutic approach in medicine. RNA can be targeted using small-molecule drugs, or RNA molecules themselves can serve as drugs by interacting with proteins or other RNA molecules. While several RNA drugs have been granted clinical approval, numerous RNA-based therapeutics are presently undergoing clinical investigation or testing for various conditions, including genetic disorders, viral infections, and diverse forms of cancer. These therapies offer several advantages, such as high specificity, enabling precise targeting of disease-related genes or proteins, cost-effectiveness, and a relatively straightforward manufacturing process. Nevertheless, successful translation of RNA therapies into widespread clinical use necessitates addressing challenges related to delivery, stability, and potential off-target effects. This chapter provides a comprehensive overview of the general concepts of various classes of RNA-based therapeutics, the mechanistic basis of their function, as well as recent applications of RNA therapeutic in clinics.
Collapse
Affiliation(s)
- Huyen Trang Ha Thi
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, Republic of Korea.
| | - Van Thai Than
- Faculty of Applied Sciences, International School, Vietnam National University, Hanoi, Vietnam; Center for Biomedicine and Community Health, International School, Vietnam National University, Hanoi, Vietnam
| |
Collapse
|
|
21
|
Bui NL, Chu DT. An introduction to RNA therapeutics and their potentials. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2024; 203:1-12. [PMID: 38359993 DOI: 10.1016/bs.pmbts.2023.12.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/17/2024]
Abstract
RNA therapeutics is a biological term regarding the usage of RNA-based molecules for medical purposes. Thanks to the success of mRNA-vaccine production against COVID-19, RNA therapeutics has gained more and more attention and investigation from worldwide scientists. It is considered as one of the promising alternatives for conventional drugs. In this first chapter, we presented an overview of the history and perspectives of RNA therapeutics' development. This chapter also explained the underlying mechanisms of different RNA-based molecules, including antisense oligonucleotide, interfering RNA (iRNA), aptamer, and mRNA, from degrading mRNA to inactivating targeted protein. Although there are many advantages of RNA therapeutics, its challenges in designing RNA chemical structure and the delivery vehicle need to be discussed. We described advanced technologies in the development of drug delivery systems that are positively correlated to the efficacy of the drug. Our aim is to provide a general background of RNA therapeutics to the audience before introducing plenty of more detailed parts, including clinical applications in certain diseases in the following chapters of the "RNA therapeutics" book.
Collapse
Affiliation(s)
- Nhat-Le Bui
- Center for Biomedicine and Community Health, International School, Vietnam National University, Hanoi, Vietnam; Faculty of Applied Sciences, International School, Vietnam National University, Hanoi, Vietnam
| | - Dinh-Toi Chu
- Center for Biomedicine and Community Health, International School, Vietnam National University, Hanoi, Vietnam; Faculty of Applied Sciences, International School, Vietnam National University, Hanoi, Vietnam.
| |
Collapse
|
|
22
|
Vu TD, Lin SC, Wu CC, Chu DT. RNA therapeutics for metabolic disorders. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2024; 203:181-196. [PMID: 38359998 DOI: 10.1016/bs.pmbts.2023.12.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/17/2024]
Abstract
The prevalence of metabolic disorders is increasing exponentially and has recently reached epidemic levels. Over the decades, a large number of therapeutic options have been proposed to manage these diseases but still show several limitations. In this circumstance, RNA therapeutics have rapidly emerged as a new hope for patients with metabolic diseases. 57 years have elapsed from the discovery of mRNA, a large number of RNA-based drug candidates have been evaluated for their therapeutic effectiveness and clinical safety under clinical studies. To date, there are seven RNA drugs for treating metabolic disorders receiving official approval and entering the global market. Their targets include hereditary transthyretin-mediated amyloidosis (hATTR), familial chylomicronemia syndrome, acute hepatic porphyria, primary hyperoxaluria type 1 and hypercholesterolemia, which are all related to liver proteins. All of these seven RNA drugs are antisense oligonucleotides (ASO) and small interfering RNA (siRNA). These two types of treatment are both based on oligonucleotides complementary to target RNA through Watson-Crick base-pairing, but their mechanisms of action include different nucleases. Such treatments show greatest potential among all types of RNA therapeutics due to consecutive achievements in chemical modifications. Another method, mRNA therapeutics also promise a brighter future for patients with a handful of drug candidates currently under development.
Collapse
Affiliation(s)
- Thuy-Duong Vu
- Center for Biomedicine and Community Health, International School, Vietnam National University, Hanoi, Vietnam
| | - Sheng-Che Lin
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Division of Plastic and Reconstructive Surgery, Tainan Municipal An-Nan Hospital-China Medical University, Tainan, Taiwan
| | - Chia-Ching Wu
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan; International Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan, Taiwan; Department of Biomedical Engineering, National Cheng Kung University, Tainan, Taiwan.
| | - Dinh-Toi Chu
- Center for Biomedicine and Community Health, International School, Vietnam National University, Hanoi, Vietnam; Faculty of Applied Sciences, International School, Vietnam National University, Hanoi, Vietnam.
| |
Collapse
|
|
23
|
Lin J, Liu J, Wang A, Si Z. A case report of acute intermittent porphyria leading to severe disability. Front Neurol 2024; 14:1334743. [PMID: 38274883 PMCID: PMC10808997 DOI: 10.3389/fneur.2023.1334743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 12/19/2023] [Indexed: 01/27/2024] Open
Abstract
Acute intermittent porphyria (AIP) is a rare inherited metabolic disorder resulting from increased production of porphyrins and their precursors, δ-aminolevulinic acid (ALA) and porphobilinogen (PBG), due to deficiencies in the enzymatic activity of the heme synthesis pathway. The disease is typically characterized by a triad of abdominal pain, neurologic impairment symptoms, and psychiatric abnormalities. However, only a small percentage of patients present with this classic triad of symptoms. Our female patient, aged 23, was admitted to the hospital with a 4-year history of abnormal mood episodes and weakness in the limbs for over 1 week. She had a previous medical history of intestinal obstruction. After admission, a cranial MRI revealed reversible posterior leukoencephalopathy imaging manifestations, and the patient exhibited weakness of the extremities, respiratory failure, seizures, and severely reduced serum sodium concentration. The diagnosis of AIP was ultimately confirmed by a positive urine PBG-sunlight test and analysis of HMBS gene variants. The absence of typical triadic signs in acute attacks of AIP can make early recognition of the disease challenging. We present a case with multiple typical clinical manifestations of AIP in the hope of aiding clinicians in fully recognizing acute intermittent porphyria.
Collapse
Affiliation(s)
- Jie Lin
- Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, Shandong Institute of Neuroimmunology, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong, China
| | - Jinzhi Liu
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Institute of Neuroimmunology, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong, China
| | - Aihua Wang
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Institute of Neuroimmunology, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong, China
| | - Zhihua Si
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Institute of Neuroimmunology, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong, China
| |
Collapse
|
|
24
|
Gogate A, Belcourt J, Shah M, Wang AZ, Frankel A, Kolmel H, Chalon M, Stephen P, Kolli A, Tawfik SM, Jin J, Bahal R, Rasmussen TP, Manautou JE, Zhong XB. Targeting the Liver with Nucleic Acid Therapeutics for the Treatment of Systemic Diseases of Liver Origin. Pharmacol Rev 2023; 76:49-89. [PMID: 37696583 PMCID: PMC10753797 DOI: 10.1124/pharmrev.123.000815] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 08/25/2023] [Accepted: 09/06/2023] [Indexed: 09/13/2023] Open
Abstract
Systemic diseases of liver origin (SDLO) are complex diseases in multiple organ systems, such as cardiovascular, musculoskeletal, endocrine, renal, respiratory, and sensory organ systems, caused by irregular liver metabolism and production of functional factors. Examples of such diseases discussed in this article include primary hyperoxaluria, familial hypercholesterolemia, acute hepatic porphyria, hereditary transthyretin amyloidosis, hemophilia, atherosclerotic cardiovascular diseases, α-1 antitrypsin deficiency-associated liver disease, and complement-mediated diseases. Nucleic acid therapeutics use nucleic acids and related compounds as therapeutic agents to alter gene expression for therapeutic purposes. The two most promising, fastest-growing classes of nucleic acid therapeutics are antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs). For each listed SDLO disease, this article discusses epidemiology, symptoms, genetic causes, current treatment options, and advantages and disadvantages of nucleic acid therapeutics by either ASO or siRNA drugs approved or under development. Furthermore, challenges and future perspectives on adverse drug reactions and toxicity of ASO and siRNA drugs for the treatment of SDLO diseases are also discussed. In summary, this review article will highlight the clinical advantages of nucleic acid therapeutics in targeting the liver for the treatment of SDLO diseases. SIGNIFICANCE STATEMENT: Systemic diseases of liver origin (SDLO) contain rare and common complex diseases caused by irregular functions of the liver. Nucleic acid therapeutics have shown promising clinical advantages to treat SDLO. This article aims to provide the most updated information on targeting the liver with antisense oligonucleotides and small interfering RNA drugs. The generated knowledge may stimulate further investigations in this growing field of new therapeutic entities for the treatment of SDLO, which currently have no or limited options for treatment.
Collapse
Affiliation(s)
- Anagha Gogate
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut
| | - Jordyn Belcourt
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut
| | - Milan Shah
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut
| | - Alicia Zongxun Wang
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut
| | - Alexis Frankel
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut
| | - Holly Kolmel
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut
| | - Matthew Chalon
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut
| | - Prajith Stephen
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut
| | - Aarush Kolli
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut
| | - Sherouk M Tawfik
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut
| | - Jing Jin
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut
| | - Raman Bahal
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut
| | - Theodore P Rasmussen
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut
| | - José E Manautou
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut
| | - Xiao-Bo Zhong
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut
| |
Collapse
|
|
25
|
Ranasinghe P, Addison ML, Dear JW, Webb DJ. Small interfering RNA: Discovery, pharmacology and clinical development-An introductory review. Br J Pharmacol 2023; 180:2697-2720. [PMID: 36250252 DOI: 10.1111/bph.15972] [Citation(s) in RCA: 57] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 08/23/2022] [Accepted: 09/29/2022] [Indexed: 11/28/2022] Open
Abstract
Post-transcriptional gene silencing targets and degrades mRNA transcripts, silencing the expression of specific genes. RNA interference technology, using synthetic structurally well-defined short double-stranded RNA (small interfering RNA [siRNA]), has advanced rapidly in recent years. This introductory review describes the utility of siRNA, by exploring the underpinning biology, pharmacology, recent advances and clinical developments, alongside potential limitations and ongoing challenges. Mediated by the RNA-induced silencing complex, siRNAs bind to specific complementary mRNAs, which are subsequently degraded. siRNA therapy offers advantages over other therapeutic approaches, including ability of specifically designed siRNAs to potentially target any mRNA and improved patient adherence through infrequent administration associated with a very long duration of action. Key pharmacokinetic and pharmacodynamic challenges include targeted administration, poor tissue penetration, nuclease inactivation, rapid renal elimination, immune activation and off-target effects. These have been overcome by chemical modification of siRNA and/or by utilising a range of delivery systems, increasing bioavailability and stability to allow successful clinical translation. Patisiran (hereditary transthyretin-mediated amyloidosis) was the first licensed siRNA, followed by givosiran (acute hepatic porphyria), lumasiran (primary hyperoxaluria type 1) and inclisiran (familial hypercholesterolaemia), which all use N-acetylgalactosamine (GalNAc) linkage for effective liver-directed delivery. Others are currently under development for indications varying from rare genetic diseases to common chronic non-communicable diseases (hypertension, cancer). Technological advances are paving the way for broader clinical use. Ongoing challenges remain in targeting organs beyond the liver and reaching special sites (e.g., brain). By overcoming these barriers, siRNA therapy has the potential to substantially widen its therapeutic impact.
Collapse
Affiliation(s)
- Priyanga Ranasinghe
- Department of Pharmacology, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka
- University/British Heart Foundation Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, UK
| | - Melisande L Addison
- University/British Heart Foundation Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, UK
| | - James W Dear
- University/British Heart Foundation Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, UK
| | - David J Webb
- University/British Heart Foundation Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, UK
| |
Collapse
|
|
26
|
Abdellatif AAH, Scagnetti G, Younis MA, Bouazzaoui A, Tawfeek HM, Aldosari BN, Almurshedi AS, Alsharidah M, Rugaie OA, Davies MPA, Liloglou T, Ross K, Saleem I. Non-coding RNA-directed therapeutics in lung cancer: Delivery technologies and clinical applications. Colloids Surf B Biointerfaces 2023; 229:113466. [PMID: 37515959 DOI: 10.1016/j.colsurfb.2023.113466] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 06/28/2023] [Accepted: 07/16/2023] [Indexed: 07/31/2023]
Abstract
Lung cancer is one of the most aggressive and deadliest health threats. There has been an increasing interest in non-coding RNA (ncRNA) recently, especially in the areas of carcinogenesis and tumour progression. However, ncRNA-directed therapies are still encountering obstacles on their way to the clinic. In the present article, we provide an overview on the potential of targeting ncRNA in the treatment of lung cancer. Then, we discuss the delivery challenges and recent approaches enabling the delivery of ncRNA-directed therapies to the lung cancer cells, where we illuminate some advanced technologies including chemically-modified oligonucleotides, nuclear targeting, and three-dimensional in vitro models. Furthermore, advanced non-viral delivery systems recruiting nanoparticles, biomimetic delivery systems, and extracellular vesicles are also highlighted. Lastly, the challenges limiting the clinical trials on the therapeutic targeting of ncRNAs in lung cancer and future directions to tackle them are explored.
Collapse
Affiliation(s)
- Ahmed A H Abdellatif
- Department of Pharmaceutics, College of Pharmacy, Qassim University, Al Qassim 51452, Saudi Arabia; Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Al-Azhar University, Assiut 71524, Egypt.
| | - Giulia Scagnetti
- School of Pharmacy & Biomolecular Sciences, Liverpool John Moores University, James Parsons Building, Liverpool L3 3AF, UK
| | - Mahmoud A Younis
- Department of Industrial Pharmacy, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt
| | - Abdellatif Bouazzaoui
- Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, Makkah 21955, Saudi Arabia; Science and Technology Unit, Umm Al-Qura University, Makkah 21955, Saudi Arabia; Medical Clinic, Hematology/Oncology, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, Regensburg 93053, Germany
| | - Hesham M Tawfeek
- Department of Industrial Pharmacy, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt
| | - Basmah N Aldosari
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Alanood S Almurshedi
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Mansour Alsharidah
- Department of Physiology, College of Medicine, Qassim University, Buraydah 51452, Saudi Arabia
| | - Osamah Al Rugaie
- Department of Basic Medical Sciences, College of Medicine and Medical Sciences, Qassim University, P.O. Box 991, Unaizah, Al Qassim 51911, Saudi Arabia
| | - Michael P A Davies
- Department of Molecular and Clinical Cancer Medicine, Institute of Systems, Molecular & Integrative Biology, The University of Liverpool, UK
| | | | - Kehinde Ross
- School of Pharmacy & Biomolecular Sciences, Liverpool John Moores University, James Parsons Building, Liverpool L3 3AF, UK; Institute for Health Research, Liverpool John Moores University, Liverpool L3 3AF, UK
| | - Imran Saleem
- School of Pharmacy & Biomolecular Sciences, Liverpool John Moores University, James Parsons Building, Liverpool L3 3AF, UK; Institute for Health Research, Liverpool John Moores University, Liverpool L3 3AF, UK.
| |
Collapse
|
|
27
|
Luo T, Huo C, Zhou T, Xie S. Progress on RNA-based therapeutics for genetic diseases. Zhejiang Da Xue Xue Bao Yi Xue Ban 2023; 52:406-416. [PMID: 37643975 PMCID: PMC10495251 DOI: 10.3724/zdxbyxb-2023-0190] [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: 04/25/2023] [Accepted: 05/31/2023] [Indexed: 08/01/2023]
Abstract
RNA therapeutics inhibit the expression of specific proteins/RNAs by targeting complementary sequences of corresponding genes or encode proteins for the synthesis desired genes to treat genetic diseases. RNA-based therapeutics are categorized as oligonucleotide drugs (antisense oligonucleotides, small interfering RNA, RNA aptamers), and mRNA drugs. The antisense oligonucleotides and small interfering RNA for treatment of genetic diseases have been approved by the FDA in the United States, while RNA aptamers and mRNA drugs are still in clinical trials. Chemical modifications can be applied to RNA drugs, such as pseudouridine modification of mRNA, to reduce immunogenicity and improve the efficacy. The secure and effective delivery systems such as lipid-based nanoparticles, extracellular vesicles, and virus-like particles are under development to address stability, specificity, and safety issues of RNA drugs. This article provides an overview of the specific molecular mechanisms of eleven RNA drugs currently used for treating genetic diseases, and discusses the research progress of chemical modifications and delivery systems of RNA drugs.
Collapse
Affiliation(s)
- Ting Luo
- Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China.
| | - Chunxiao Huo
- Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Tianhua Zhou
- Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China.
- The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Center for RNA Medicine, International Institutes of Medicine, Zhejiang University, Jinhua 322000, Zhejiang Province, China.
- Zhejiang University Cancer Center, Hangzhou 310058, China.
| | - Shanshan Xie
- Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, China.
| |
Collapse
|
|
28
|
Valbuena Valecillos A, Yatham P, Alderman M, Shapiro L, Tiozzo E, Gober J. Acute Intermittent Porphyria: A Review and Rehabilitation Perspective. Cureus 2023; 15:e44260. [PMID: 37772218 PMCID: PMC10526832 DOI: 10.7759/cureus.44260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/27/2023] [Indexed: 09/30/2023] Open
Abstract
Acute intermittent porphyria (AIP) is an uncommon metabolic disease that impacts multiple organs and can manifest in many ways. It is often misdiagnosed due to its nonspecific symptoms. Neurovisceral signs and symptoms should alert physicians to consider AIP in the differential after excluding more common causes. Identifying the underlying cause is critical in preventing acute attacks, and trigger avoidance is the optimal approach to managing AIP. Medications that are contraindicated should be reviewed thoroughly. Prompt intravenous hematin administration is the primary treatment for acute attacks, and additional pharmacological therapies may be necessary to treat concurrent symptoms. A severe neurological manifestation of AIP is flaccid paralysis or severe motor weakness, which can develop into total quadriplegia and respiratory insufficiency. A comprehensive rehabilitation program is an integral aspect of the treatment plan. Since the incidence of this disease is low, functional prognosis is not well-known. As a result, it is challenging to determine the most appropriate structure, intensity, and duration of rehabilitation therapy. By extending the treatment plan, individuals with tetraplegia due to AIP can continue to make functional gains years after the onset of weakness. Understanding the disease's functional prognosis will aid in coordinating resources and improving healthcare expenditures.
Collapse
Affiliation(s)
- Adriana Valbuena Valecillos
- Department of Physical Medicine and Rehabilitation, University of Miami Miller School of Medicine/Jackson Memorial Hospital, Miami, USA
| | - Puja Yatham
- Department of Medicine, Herbert Wertheim College of Medicine, Miami, USA
| | - Matison Alderman
- Department of Physical Medicine and Rehabilitation, University of Miami Miller School of Medicine/Jackson Memorial Hospital, Miami, USA
| | - Lauren Shapiro
- Department of Physical Medicine and Rehabilitation, University of Miami Miller School of Medicine/Jackson Memorial Hospital, Miami, USA
| | - Eduard Tiozzo
- Department of Physical Medicine and Rehabilitation, University of Miami Miller School of Medicine/Jackson Memorial Hospital, Miami, USA
| | - Joslyn Gober
- Department of Physical Medicine and Rehabilitation, University of Miami Miller School of Medicine/Jackson Memorial Hospital, Miami, USA
| |
Collapse
|
|
29
|
Abdelaziz N, Therachiyil L, Sadida HQ, Ali AM, Khan OS, Singh M, Khan AQ, Akil ASAS, Bhat AA, Uddin S. Epigenetic inhibitors and their role in cancer therapy. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2023; 380:211-251. [PMID: 37657859 DOI: 10.1016/bs.ircmb.2023.04.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/03/2023]
Abstract
Epigenetic modifications to DNA are crucial for normal cellular and biological functioning. DNA methylation, histone modifications, and chromatin remodeling are the most common epigenetic mechanisms. These changes are heritable but still reversible. The aberrant epigenetic alterations, such as DNA methylation, histone modification, and non-coding RNA (ncRNA)-mediated gene regulation, play an essential role in developing various human diseases, including cancer. Recent studies show that synthetic and dietary epigenetic inhibitors attenuate the abnormal epigenetic modifications in cancer cells and therefore have strong potential for cancer treatment. In this chapter, we have highlighted various types of epigenetic modifications, their mechanism, and as drug targets for epigenetic therapy.
Collapse
Affiliation(s)
- Nouha Abdelaziz
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Lubna Therachiyil
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha, Qatar
| | - Hana Q Sadida
- Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Program, Sidra Medicine, Doha, Qatar
| | | | - Omar S Khan
- Chicago College of Osteopathic Medicine, Midwestern University, Downers Grove, IL, USA
| | - Mayank Singh
- Department of Medical Oncology (Lab), BRAIRCH All India Institute of Medical Sciences (AIIMS), New Delhi, India
| | - Abdul Q Khan
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Ammira S Al-Shabeeb Akil
- Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Program, Sidra Medicine, Doha, Qatar
| | - Ajaz A Bhat
- Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Program, Sidra Medicine, Doha, Qatar.
| | - Shahab Uddin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Department of Biosciences, Integral University, Lucknow, Uttar Pradesh, India.
| |
Collapse
|
|
30
|
Kurakula H, Vaishnavi S, Sharif MY, Ellipilli S. Emergence of Small Interfering RNA-Based Gene Drugs for Various Diseases. ACS OMEGA 2023; 8:20234-20250. [PMID: 37323391 PMCID: PMC10268023 DOI: 10.1021/acsomega.3c01703] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 05/22/2023] [Indexed: 06/17/2023]
Abstract
Small molecule, peptide, and protein-based drugs have been developed over decades to treat various diseases. The importance of gene therapy as an alternative to traditional drugs has increased after the discovery of gene-based drugs such as Gendicine for cancer and Neovasculgen for peripheral artery disease. Since then, the pharma sector is focusing on developing gene-based drugs for various diseases. After the discovery of the RNA interference (RNAi) mechanism, the development of siRNA-based gene therapy has been accelerated immensely. siRNA-based treatment for hereditary transthyretin-mediated amyloidosis (hATTR) using Onpattro and acute hepatic porphyria (AHP) by Givlaari and three more FDA-approved siRNA drugs has set up a milestone and further improved the confidence for the development of gene therapeutics for a spectrum of diseases. siRNA-based gene drugs have more advantages over other gene therapies and are under study to treat different types of diseases such as viral infections, cardiovascular diseases, cancer, and many more. However, there are a few bottlenecks to realizing the full potential of siRNA-based gene therapy. They include chemical instability, nontargeted biodistribution, undesirable innate immune responses, and off-target effects. This review provides a comprehensive view of siRNA-based gene drugs: challenges associated with siRNA delivery, their potential, and future prospects.
Collapse
Affiliation(s)
- Harshini Kurakula
- Department
of Chemistry, School of Engineering and Sciences, SRM University-AP, Amaravati, Andhra Pradesh 522240, India
| | - Swetha Vaishnavi
- Department
of Chemistry, School of Engineering and Sciences, SRM University-AP, Amaravati, Andhra Pradesh 522240, India
| | - Mohammed Yaseen Sharif
- Department
of Chemistry, School of Engineering and Sciences, SRM University-AP, Amaravati, Andhra Pradesh 522240, India
| | - Satheesh Ellipilli
- Department
of Chemistry, School of Engineering and Sciences, SRM University-AP, Amaravati, Andhra Pradesh 522240, India
| |
Collapse
|
|
31
|
Leusmann S, Ménová P, Shanin E, Titz A, Rademacher C. Glycomimetics for the inhibition and modulation of lectins. Chem Soc Rev 2023; 52:3663-3740. [PMID: 37232696 PMCID: PMC10243309 DOI: 10.1039/d2cs00954d] [Citation(s) in RCA: 48] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Indexed: 05/27/2023]
Abstract
Carbohydrates are essential mediators of many processes in health and disease. They regulate self-/non-self- discrimination, are key elements of cellular communication, cancer, infection and inflammation, and determine protein folding, function and life-times. Moreover, they are integral to the cellular envelope for microorganisms and participate in biofilm formation. These diverse functions of carbohydrates are mediated by carbohydrate-binding proteins, lectins, and the more the knowledge about the biology of these proteins is advancing, the more interfering with carbohydrate recognition becomes a viable option for the development of novel therapeutics. In this respect, small molecules mimicking this recognition process become more and more available either as tools for fostering our basic understanding of glycobiology or as therapeutics. In this review, we outline the general design principles of glycomimetic inhibitors (Section 2). This section is then followed by highlighting three approaches to interfere with lectin function, i.e. with carbohydrate-derived glycomimetics (Section 3.1), novel glycomimetic scaffolds (Section 3.2) and allosteric modulators (Section 3.3). We summarize recent advances in design and application of glycomimetics for various classes of lectins of mammalian, viral and bacterial origin. Besides highlighting design principles in general, we showcase defined cases in which glycomimetics have been advanced to clinical trials or marketed. Additionally, emerging applications of glycomimetics for targeted protein degradation and targeted delivery purposes are reviewed in Section 4.
Collapse
Affiliation(s)
- Steffen Leusmann
- Chemical Biology of Carbohydrates (CBCH), Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research, 66123 Saarbrücken, Germany.
- Department of Chemistry, Saarland University, 66123 Saarbrücken, Germany
- Deutsches Zentrum für Infektionsforschung (DZIF), Standort Hannover-Braunschweig, Germany
| | - Petra Ménová
- University of Chemistry and Technology, Prague, Technická 5, 16628 Prague 6, Czech Republic
| | - Elena Shanin
- Department of Pharmaceutical Sciences, University of Vienna, Josef-Holaubek-Platz 2, 1090 Vienna, Austria.
- Department of Microbiology, Immunobiology and Genetics, Max F. Perutz Laboratories, University of Vienna, Biocenter 5, 1030 Vienna, Austria
| | - Alexander Titz
- Chemical Biology of Carbohydrates (CBCH), Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research, 66123 Saarbrücken, Germany.
- Department of Chemistry, Saarland University, 66123 Saarbrücken, Germany
- Deutsches Zentrum für Infektionsforschung (DZIF), Standort Hannover-Braunschweig, Germany
| | - Christoph Rademacher
- Department of Pharmaceutical Sciences, University of Vienna, Josef-Holaubek-Platz 2, 1090 Vienna, Austria.
- Department of Microbiology, Immunobiology and Genetics, Max F. Perutz Laboratories, University of Vienna, Biocenter 5, 1030 Vienna, Austria
| |
Collapse
|
|
32
|
Niazi SK. RNA Therapeutics: A Healthcare Paradigm Shift. Biomedicines 2023; 11:biomedicines11051275. [PMID: 37238946 DOI: 10.3390/biomedicines11051275] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 04/14/2023] [Accepted: 04/21/2023] [Indexed: 05/28/2023] Open
Abstract
COVID-19 brought about the mRNA vaccine and a paradigm shift to a new mode of treating and preventing diseases. Synthetic RNA products are a low-cost solution based on a novel method of using nucleosides to act as an innate medicine factory with unlimited therapeutic possibilities. In addition to the common perception of vaccines preventing infections, the newer applications of RNA therapies include preventing autoimmune disorders, such as diabetes, Parkinson's disease, Alzheimer's disease, and Down syndrome; now, we can deliver monoclonal antibodies, hormones, cytokines, and other complex proteins, reducing the manufacturing hurdles associated with these products. Newer PCR technology removes the need for the bacterial expression of DNA, making mRNA a truly synthetic product. AI-driven product design expands the applications of mRNA technology to repurpose therapeutic proteins and test their safety and efficacy quickly. As the industry focuses on mRNA, many novel opportunities will arise, as hundreds of products under development will bring new perspectives based on this significant paradigm shift-finding newer solutions to existing challenges in healthcare.
Collapse
Affiliation(s)
- Sarfaraz K Niazi
- College of Pharmacy, University of Illinois, Chicago, IL 60612, USA
| |
Collapse
|
|
33
|
Xiao Y, Liu TM, MacRae IJ. A tiny loop in the Argonaute PIWI domain tunes small RNA seed strength. EMBO Rep 2023:e55806. [PMID: 37082939 DOI: 10.15252/embr.202255806] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 03/29/2023] [Accepted: 04/05/2023] [Indexed: 04/22/2023] Open
Abstract
Argonaute (AGO) proteins use microRNAs (miRNAs) and small interfering RNAs (siRNAs) as guides to regulate gene expression in plants and animals. AGOs that use miRNAs in bilaterian animals recognize short (6-8 nt.) elements complementary to the miRNA seed region, enabling each miRNA to interact with hundreds of otherwise unrelated targets. By contrast, AGOs that use miRNAs in plants employ longer (> 13 nt.) recognition elements such that each miRNA silences a small number of physiologically related targets. Here, we show that this major functional distinction depends on a minor structural difference between plant and animal AGO proteins: a 9-amino acid loop in the PIWI domain. Swapping the PIWI loop from human Argonaute2 (HsAGO2) into Arabidopsis Argonaute10 (AtAGO10) increases seed strength, resulting in animal-like miRNA targeting. Conversely, swapping the plant PIWI loop into HsAGO2 reduces seed strength and accelerates the turnover of cleaved targets. The loop-swapped HsAGO2 silences targets more potently, with reduced miRNA-like targeting, than wild-type HsAGO2 in mammalian cells. Thus, tiny structural differences can tune the targeting properties of AGO proteins for distinct biological roles.
Collapse
Affiliation(s)
- Yao Xiao
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA
| | - TingYu M Liu
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA
| | - Ian J MacRae
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA
| |
Collapse
|
|
34
|
Anwar S, Mir F, Yokota T. Enhancing the Effectiveness of Oligonucleotide Therapeutics Using Cell-Penetrating Peptide Conjugation, Chemical Modification, and Carrier-Based Delivery Strategies. Pharmaceutics 2023; 15:pharmaceutics15041130. [PMID: 37111616 PMCID: PMC10140998 DOI: 10.3390/pharmaceutics15041130] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 03/28/2023] [Accepted: 03/28/2023] [Indexed: 04/29/2023] Open
Abstract
Oligonucleotide-based therapies are a promising approach for treating a wide range of hard-to-treat diseases, particularly genetic and rare diseases. These therapies involve the use of short synthetic sequences of DNA or RNA that can modulate gene expression or inhibit proteins through various mechanisms. Despite the potential of these therapies, a significant barrier to their widespread use is the difficulty in ensuring their uptake by target cells/tissues. Strategies to overcome this challenge include cell-penetrating peptide conjugation, chemical modification, nanoparticle formulation, and the use of endogenous vesicles, spherical nucleic acids, and smart material-based delivery vehicles. This article provides an overview of these strategies and their potential for the efficient delivery of oligonucleotide drugs, as well as the safety and toxicity considerations, regulatory requirements, and challenges in translating these therapies from the laboratory to the clinic.
Collapse
Affiliation(s)
- Saeed Anwar
- Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada
| | - Farin Mir
- Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada
| | - Toshifumi Yokota
- Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada
| |
Collapse
|
|
35
|
Rakocevic J, Dobric M, Vucic R, Furtula M, Zaletel I, Milutinovic K, Ilijevski A, Borovic ML, Tomasevic M, Bajcetic M. Small Interfering Ribonucleic Acid as Lipid-Lowering Therapy: Inclisiran in Focus. Int J Mol Sci 2023; 24:6012. [PMID: 36983086 PMCID: PMC10056056 DOI: 10.3390/ijms24066012] [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: 02/22/2023] [Revised: 03/11/2023] [Accepted: 03/13/2023] [Indexed: 03/30/2023] Open
Abstract
The PCSK9 (Proprotein Convertase Subtilisin/Kexin type 9) enzyme interferes with the metabolism of low-density lipoprotein (LDL) cholesterol. Inhibition of PCSK9 results in lower LDL cholesterol levels, which can be achieved by different molecular pathways. Monoclonal antibodies targeting circulating PCSK9 have shown strong and persistent effects on lowering the LDL cholesterol level, while reducing the risk of future cardiovascular events. However, this therapy requires once- or twice-monthly administration in the form of subcutaneous injection. This dosing regimen might impact the therapy adherence in cardiovascular patients who often require multiple drugs with different dosing intervals. Small interfering ribonucleic acid (siRNA) represents a promising therapy approach for patients with elevated LDL cholesterol level despite optimized background statin therapy. Inclisiran is a synthesized siRNA which inhibits PCSK9 synthesis in the liver and provides sustained and durable lowering of LDL cholesterol with twice-yearly application and a good tolerability profile. Herein, we present an overview of the current available data and critical review of the major clinical trials which assessed safety and efficacy of inclisiran in different groups of patients with elevated LDL cholesterol level.
Collapse
Affiliation(s)
- Jelena Rakocevic
- Institute of Histology and Embryology “Aleksandar Đ. Kostić”, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (J.R.)
| | - Milan Dobric
- Institute for Cardiovascular Diseases “Dedinje”, 11000 Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Rada Vucic
- Cardiology Clinic, University Clinical Center Kragujevac, 34000 Kragujevac, Serbia
- Department of Internal Medicine, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
| | - Matija Furtula
- Institute for Cardiovascular Diseases “Dedinje”, 11000 Belgrade, Serbia
| | - Ivan Zaletel
- Institute of Histology and Embryology “Aleksandar Đ. Kostić”, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (J.R.)
| | - Katarina Milutinovic
- Institute of Histology and Embryology “Aleksandar Đ. Kostić”, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (J.R.)
| | - Ana Ilijevski
- Institute of Histology and Embryology “Aleksandar Đ. Kostić”, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (J.R.)
| | - Milica Labudovic Borovic
- Institute of Histology and Embryology “Aleksandar Đ. Kostić”, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (J.R.)
| | - Miloje Tomasevic
- Department of Internal Medicine, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
- Cardiology Clinic, University Clinical Center of Serbia, 11000 Belgrade, Serbia
| | - Milos Bajcetic
- Institute of Histology and Embryology “Aleksandar Đ. Kostić”, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (J.R.)
| |
Collapse
|
|
36
|
Zhang X, Cattoglio C, Zoltek M, Vetralla C, Mozumdar D, Schepartz A. Dose-Dependent Nuclear Delivery and Transcriptional Repression with a Cell-Penetrant MeCP2. ACS CENTRAL SCIENCE 2023; 9:277-288. [PMID: 36844491 PMCID: PMC9951310 DOI: 10.1021/acscentsci.2c01226] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Indexed: 06/13/2023]
Abstract
The vast majority of biologic-based therapeutics operate within serum, on the cell surface, or within endocytic vesicles, in large part because proteins and nucleic acids fail to efficiently cross cell or endosomal membranes. The impact of biologic-based therapeutics would expand exponentially if proteins and nucleic acids could reliably evade endosomal degradation, escape endosomal vesicles, and remain functional. Using the cell-permeant mini-protein ZF5.3, here we report the efficient nuclear delivery of functional Methyl-CpG-binding-protein 2 (MeCP2), a transcriptional regulator whose mutation causes Rett syndrome (RTT). We report that ZF-tMeCP2, a conjugate of ZF5.3 and MeCP2(Δaa13-71, 313-484), binds DNA in a methylation-dependent manner in vitro, and reaches the nucleus of model cell lines intact to achieve an average concentration of 700 nM. When delivered to live cells, ZF-tMeCP2 engages the NCoR/SMRT corepressor complex, selectively represses transcription from methylated promoters, and colocalizes with heterochromatin in mouse primary cortical neurons. We also report that efficient nuclear delivery of ZF-tMeCP2 relies on an endosomal escape portal provided by HOPS-dependent endosomal fusion. The Tat conjugate of MeCP2 (Tat-tMeCP2), evaluated for comparison, is degraded within the nucleus, is not selective for methylated promoters, and trafficks in a HOPS-independent manner. These results support the feasibility of a HOPS-dependent portal for delivering functional macromolecules to the cell interior using the cell-penetrant mini-protein ZF5.3. Such a strategy could broaden the impact of multiple families of biologic-based therapeutics.
Collapse
Affiliation(s)
- Xizi Zhang
- Department
of Chemistry, University of California, Berkeley, California 94720, United States
| | - Claudia Cattoglio
- Department
of Molecular and Cellular Biology, University
of California, Berkeley, California 94720, United States
- Howard
Hughes Medical Institute, University of
California, Berkeley, California 94720, United States
| | - Madeline Zoltek
- Department
of Molecular and Cellular Biology, University
of California, Berkeley, California 94720, United States
| | - Carlo Vetralla
- Department
of Molecular and Cellular Biology, University
of California, Berkeley, California 94720, United States
- Howard
Hughes Medical Institute, University of
California, Berkeley, California 94720, United States
| | - Deepto Mozumdar
- Department
of Chemistry, University of California, Berkeley, California 94720, United States
- Department
of Chemistry, Yale University, New Haven, Connecticut 06520, United States
| | - Alanna Schepartz
- Department
of Chemistry, University of California, Berkeley, California 94720, United States
- Department
of Molecular and Cellular Biology, University
of California, Berkeley, California 94720, United States
- California
Institute for Quantitative Biosciences (QB3), University of California, Berkeley, California 94720, United States
- Chan Zuckerberg
Biohub, San Francisco, California 94158, United States
| |
Collapse
|
|
37
|
Inclisiran-Safety and Effectiveness of Small Interfering RNA in Inhibition of PCSK-9. Pharmaceutics 2023; 15:pharmaceutics15020323. [PMID: 36839644 PMCID: PMC9965021 DOI: 10.3390/pharmaceutics15020323] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 01/11/2023] [Accepted: 01/14/2023] [Indexed: 01/20/2023] Open
Abstract
Dyslipidemia is listed among important cardiovascular disease risk factors. Treating lipid disorders is difficult, and achieving desirable levels of LDL-cholesterol (LDL-C) is essential in both the secondary and primary prevention of cardiovascular disease. For many years, statins became the basis of lipid-lowering therapy. Nevertheless, these drugs are often insufficient due to their side effects and restrictive criteria for achieving the recommended LDL-C values. Even the addition of other drugs, i.e., ezetimibe, does not help one achieve the target LDL-C. The discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) discovery has triggered intensive research on a new class of protein-based drugs. The protein PCSK9 is located mainly in hepatocytes and is involved in the metabolism of LDL-C. In the beginning, antibodies against the PCSK9 protein, such as evolocumab, were invented. The next step was inclisiran. Inclisiran is a small interfering RNA (siRNA) that inhibits the expression of PCSK9 by binding specifically to the mRNA precursor of PCSK9 protein and causing its degradation. It has been noticed in recent years that siRNA is a powerful tool for biomedical research and drug discovery. The purpose of this work is to summarize the molecular mechanisms, pharmacokinetics, pharmacodynamics of inclisiran and to review the latest research.
Collapse
|
|
38
|
Rios A, Kehrberg L, Davis HE. Consideration of Acute Porphyria in an Emergency Department Patient: A Case Report and Discussion of Common Pitfalls. Clin Pract Cases Emerg Med 2022; 6:310-313. [PMID: 36427037 PMCID: PMC9697880 DOI: 10.5811/cpcem.2022.9.57507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 09/20/2022] [Indexed: 11/18/2022] Open
Abstract
INTRODUCTION Porphyria refers to a group of disorders associated with defects in heme synthesis. They can be associated with severely debilitating features, including abdominal pain, psychiatric symptoms, neurological defects, and cardiovascular irregularities. Although these diseases are rare, patients with attacks often do present to the emergency department (ED) where consideration of porphyria is generally not included in the differential. CASE REPORT Here, we examine a case of a 16-year-old male who presented to our ED for evaluation of recurring abdominal pain and auditory hallucinations in which porphyria was considered by the emergency physician. DISCUSSION Not considering acute porphyria in patients with recurring neurovisceral symptoms in the ED can lead to missed opportunities for diagnosing such pathologies.
Collapse
Affiliation(s)
- Anthony Rios
- University of Tennessee, Department of Biochemistry, Knoxville, Tennessee,University of Tennessee Medical Center, Department of Emergency Medicine, Knoxville, Tennessee
| | | | - Hillary E. Davis
- University of Tennessee Medical Center, Department of Emergency Medicine, Knoxville, Tennessee
| |
Collapse
|
|
39
|
Abosalha AK, Boyajian J, Ahmad W, Islam P, Ghebretatios M, Schaly S, Thareja R, Arora K, Prakash S. Clinical pharmacology of siRNA therapeutics: current status and future prospects. Expert Rev Clin Pharmacol 2022; 15:1327-1341. [PMID: 36251525 DOI: 10.1080/17512433.2022.2136166] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Small interfering RNA (siRNA) has emerged as a powerful tool for post-transcriptional downregulation of multiple genes for various therapies. Naked siRNA molecules are surrounded by several barriers that tackle their optimum delivery to target tissues such as limited cellular uptake, short circulation time, degradation by endonucleases, glomerular filtration, and capturing by the reticuloendothelial system (RES). AREAS COVERED This review provides insights into studies that investigate various siRNA-based therapies, focusing on the mechanism, delivery strategies, bioavailability, pharmacokinetic, and pharmacodynamics of naked and modified siRNA molecules. The clinical pharmacology of currently approved siRNA products is also discussed. EXPERT OPINION Few siRNA-based products have been approved recently by the Food and Drug Administration (FDA) and other regulatory agencies after approximately twenty years following its discovery due to the associated limitations. The absorption, distribution, metabolism, and excretion of siRNA therapeutics are highly restricted by several obstacles, resulting in rapid clearance of siRNA-based therapeutic products from systemic circulation before reaching the cytosol of targeted cells. The siRNA therapeutics however are very promising in many diseases, including gene therapy and SARS-COV-2 viral infection. The design of suitable delivery vehicles and developing strategies toward better pharmacokinetic parameters may solve the challenges of siRNA therapies.
Collapse
Affiliation(s)
- Ahmed Khaled Abosalha
- Biomedical Technology and Cell Therapy Research Laboratory, Department of Biomedical Engineering, Faculty of Medicine, McGill University, Montreal, Quebec, H3A 2B4, Canada.,Pharmaceutical Technology Department, Faculty of Pharmacy, Tanta University, Tanta, Egypt
| | - Jacqueline Boyajian
- Biomedical Technology and Cell Therapy Research Laboratory, Department of Biomedical Engineering, Faculty of Medicine, McGill University, Montreal, Quebec, H3A 2B4, Canada
| | - Waqar Ahmad
- Biomedical Technology and Cell Therapy Research Laboratory, Department of Biomedical Engineering, Faculty of Medicine, McGill University, Montreal, Quebec, H3A 2B4, Canada
| | - Paromita Islam
- Biomedical Technology and Cell Therapy Research Laboratory, Department of Biomedical Engineering, Faculty of Medicine, McGill University, Montreal, Quebec, H3A 2B4, Canada
| | - Merry Ghebretatios
- Biomedical Technology and Cell Therapy Research Laboratory, Department of Biomedical Engineering, Faculty of Medicine, McGill University, Montreal, Quebec, H3A 2B4, Canada
| | - Sabrina Schaly
- Biomedical Technology and Cell Therapy Research Laboratory, Department of Biomedical Engineering, Faculty of Medicine, McGill University, Montreal, Quebec, H3A 2B4, Canada
| | - Rahul Thareja
- Biomedical Technology and Cell Therapy Research Laboratory, Department of Biomedical Engineering, Faculty of Medicine, McGill University, Montreal, Quebec, H3A 2B4, Canada
| | - Karan Arora
- Biomedical Technology and Cell Therapy Research Laboratory, Department of Biomedical Engineering, Faculty of Medicine, McGill University, Montreal, Quebec, H3A 2B4, Canada
| | - Satya Prakash
- Biomedical Technology and Cell Therapy Research Laboratory, Department of Biomedical Engineering, Faculty of Medicine, McGill University, Montreal, Quebec, H3A 2B4, Canada
| |
Collapse
|
|
40
|
Abstract
The highly specific induction of RNA interference-mediated gene knockdown, based on the direct application of small interfering RNAs (siRNAs), opens novel avenues towards innovative therapies. Two decades after the discovery of the RNA interference mechanism, the first siRNA drugs received approval for clinical use by the US Food and Drug Administration and the European Medicines Agency between 2018 and 2022. These are mainly based on an siRNA conjugation with a targeting moiety for liver hepatocytes, N-acetylgalactosamine, and cover the treatment of acute hepatic porphyria, transthyretin-mediated amyloidosis, hypercholesterolemia, and primary hyperoxaluria type 1. Still, the development of siRNA therapeutics faces several challenges and issues, including the definition of optimal siRNAs in terms of target, sequence, and chemical modifications, siRNA delivery to its intended site of action, and the absence of unspecific off-target effects. Further siRNA drugs are in clinical studies, based on different delivery systems and covering a wide range of different pathologies including metabolic diseases, hematology, infectious diseases, oncology, ocular diseases, and others. This article reviews the knowledge on siRNA design and chemical modification, as well as issues related to siRNA delivery that may be addressed using different delivery systems. Details on the mode of action and clinical status of the various siRNA therapeutics are provided, before giving an outlook on issues regarding the future of siRNA drugs and on their potential as one emerging standard modality in pharmacotherapy. Notably, this may also cover otherwise un-druggable diseases, the definition of non-coding RNAs as targets, and novel concepts of personalized and combination treatment regimens.
Collapse
Affiliation(s)
- Maik Friedrich
- Faculty of Leipzig, Institute of Clinical Immunology, Max-Bürger-Forschungszentrum (MBFZ), University of Leipzig, Leipzig, Germany.,Department of Vaccines and Infection Models, Fraunhofer Institute for Cell Therapy and Immunology IZI, Leipzig, Germany
| | - Achim Aigner
- Rudolf-Boehm Institute for Pharmacology and Toxicology, Clinical Pharmacology, University of Leipzig, Haertelstrasse 16-18, 04107, Leipzig, Germany.
| |
Collapse
|
|
41
|
Bege M, Borbás A. The Medicinal Chemistry of Artificial Nucleic Acids and Therapeutic Oligonucleotides. Pharmaceuticals (Basel) 2022; 15:ph15080909. [PMID: 35893733 PMCID: PMC9330994 DOI: 10.3390/ph15080909] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 07/17/2022] [Accepted: 07/20/2022] [Indexed: 02/04/2023] Open
Abstract
Nucleic acids play a central role in human biology, making them suitable and attractive tools for therapeutic applications. While conventional drugs generally target proteins and induce transient therapeutic effects, nucleic acid medicines can achieve long-lasting or curative effects by targeting the genetic bases of diseases. However, native oligonucleotides are characterized by low in vivo stability due to nuclease sensitivity and unfavourable physicochemical properties due to their polyanionic nature, which are obstacles to their therapeutic use. A myriad of synthetic oligonucleotides have been prepared in the last few decades and it has been shown that proper chemical modifications to either the nucleobase, the ribofuranose unit or the phosphate backbone can protect the nucleic acids from degradation, enable efficient cellular uptake and target localization ensuring the efficiency of the oligonucleotide-based therapy. In this review, we present a summary of structure and properties of artificial nucleic acids containing nucleobase, sugar or backbone modifications, and provide an overview of the structure and mechanism of action of approved oligonucleotide drugs including gene silencing agents, aptamers and mRNA vaccines.
Collapse
Affiliation(s)
- Miklós Bege
- Department of Pharmaceutical Chemistry, University of Debrecen, Egyetem tér 1, 4032 Debrecen, Hungary;
- Institute of Healthcare Industry, University of Debrecen, Nagyerdei körút 98, 4032 Debrecen, Hungary
- MTA-DE Molecular Recognition and Interaction Research Group, University of Debrecen, Egyetem tér 1, 4032 Debrecen, Hungary
| | - Anikó Borbás
- Department of Pharmaceutical Chemistry, University of Debrecen, Egyetem tér 1, 4032 Debrecen, Hungary;
- National Laboratory of Virology, University of Pécs, Ifjúság útja 20, 7624 Pécs, Hungary
- Correspondence:
| |
Collapse
|
|
42
|
Neurological Manifestations of Acute Porphyrias. Curr Neurol Neurosci Rep 2022; 22:355-362. [PMID: 35665475 DOI: 10.1007/s11910-022-01205-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/21/2022] [Indexed: 11/03/2022]
Abstract
PURPOSE OF REVIEW Porphyrias constitute a group of rare metabolic disorders that result in a deficiency of the heme biosynthetic pathway and lead to the accumulation of metabolic intermediaries. Patients with porphyria can experience recurrent neurovisceral attacks which are characterized by neuropathic abdominal pain and acute gastrointestinal symptoms, including nausea, vomiting, and constipation. Depending on the type of porphyria, patients can present with cutaneous manifestations, such as severe skin photosensitivity, chronic hemolysis, or evidence of neurologic dysfunction, including alterations in consciousness, neurovascular involvement, seizures, transient sensor-motor symptoms, polyneuropathy, and behavioral abnormalities. RECENT FINDINGS More recently, cases of posterior reversible encephalopathy syndrome, cerebral vasoconstriction, and acute flaccid paralysis have also been described. While the exact pathogenic mechanisms linking the accumulation of abnormal heme biosynthetic intermediaries to neurologic manifestations have not been completely elucidated, it has been proposed that these manifestations are more common than previously thought and can result in permanent neurologic injury. This article reviews the basic principles of heme synthesis as well as the pathogenic mechanism of disease, presentation, and treatment of acute hepatic porphyrias with emphasis on those with neurologic manifestations.
Collapse
|
|
43
|
Majeed CN, Ma CD, Xiao T, Rudnick S, Bonkovsky HL. Spotlight on Givosiran as a Treatment Option for Adults with Acute Hepatic Porphyria: Design, Development, and Place in Therapy. Drug Des Devel Ther 2022; 16:1827-1845. [PMID: 35734365 PMCID: PMC9208469 DOI: 10.2147/dddt.s281631] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Accepted: 04/23/2022] [Indexed: 12/13/2022] Open
Abstract
Small interfering ribonucleic acids [siRNAs] are short ribonucleic acid (RNA) fragments cleaved from double-stranded RNA molecules that target and bind to specific sequences on messenger RNA (mRNA), leading to their destruction. Therefore, the siRNA down-regulates the formation of selected mRNAs and their protein products. Givosiran is one such siRNA that uses this mechanism to treat acute hepatic porphyrias. Acute hepatic porphyrias are a group of rare, inherited metabolic disorders, characterized by acute potentially life-threatening attacks as well as chronic symptoms with a negative impact on quality of life. It has four types, each associated with distinct enzyme defects in the heme biosynthesis pathway in the liver. By targeting the expression of hepatic 5-aminolevulinic acid [ALA] synthase-1 [ALAS1], givosiran can down-regulate levels of toxic metabolites, leading to biochemical and clinical improvement. Givosiran selectively targets hepatocytes due to its linkage to N-acetylgalactosamine (GalNac) leading to its selective uptake via asialoglycoprotein receptors (ASGPR). We provide an up-to-date literature review regarding givosiran in the context of a clinical overview of the porphyrias, an overview of siRNAs for therapy of human disorders, the design and development of givosiran, key clinical trial results of givosiran for prevention of acute porphyric attacks, emerging concerns regarding chronic use of givosiran, and the overall management of acute hepatic porphyrias. These insights are important not only for the management of acute hepatic porphyrias but also for the emerging field of siRNAs and their role in novel therapies for various diseases.
Collapse
Affiliation(s)
- Chaudry Nasir Majeed
- Department of Internal Medicine, Section on Gastroenterology and Hepatology, Wake Forest School of Medicine, Winston-Salem, NC, USA
- Correspondence: Chaudry Nasir Majeed, Department of Internal Medicine, Section on Gastroenterology and Hepatology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, 27157, USA, Tel +1 (336) 713-7311, Fax +1 (336) 713-7322, Email
| | - Christopher D Ma
- Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Ted Xiao
- Department of Internal Medicine, Internal Medicine Residency Program, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Sean Rudnick
- Department of Internal Medicine, Section on Gastroenterology and Hepatology, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Herbert L Bonkovsky
- Department of Internal Medicine, Section on Gastroenterology and Hepatology, Wake Forest School of Medicine, Winston-Salem, NC, USA
| |
Collapse
|
|
44
|
Zogg H, Singh R, Ro S. Current Advances in RNA Therapeutics for Human Diseases. Int J Mol Sci 2022; 23:2736. [PMID: 35269876 PMCID: PMC8911101 DOI: 10.3390/ijms23052736] [Citation(s) in RCA: 100] [Impact Index Per Article: 33.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 02/25/2022] [Accepted: 02/25/2022] [Indexed: 12/11/2022] Open
Abstract
Following the discovery of nucleic acids by Friedrich Miescher in 1868, DNA and RNA were recognized as the genetic code containing the necessary information for proper cell functioning. In the years following these discoveries, vast knowledge of the seemingly endless roles of RNA have become better understood. Additionally, many new types of RNAs were discovered that seemed to have no coding properties (non-coding RNAs), such as microRNAs (miRNAs). The discovery of these new RNAs created a new avenue for treating various human diseases. However, RNA is relatively unstable and is degraded fairly rapidly once administered; this has led to the development of novel delivery mechanisms, such as nanoparticles to increase stability as well as to prevent off-target effects of these molecules. Current advances in RNA-based therapies have substantial promise in treating and preventing many human diseases and disorders through fixing the pathology instead of merely treating the symptomology similarly to traditional therapeutics. Although many RNA therapeutics have made it to clinical trials, only a few have been FDA approved thus far. Additionally, the results of clinical trials for RNA therapeutics have been ambivalent to date, with some studies demonstrating potent efficacy, whereas others have limited effectiveness and/or toxicity. Momentum is building in the clinic for RNA therapeutics; future clinical care of human diseases will likely comprise promising RNA therapeutics. This review focuses on the current advances of RNA therapeutics and addresses current challenges with their development.
Collapse
Affiliation(s)
| | | | - Seungil Ro
- Department of Physiology and Cell Biology, Reno School of Medicine, University of Nevada, 1664 North Virginia Street, Reno, NV 89557, USA; (H.Z.); (R.S.)
| |
Collapse
|
|
45
|
Vera-Yunca D, Córdoba KM, Parra-Guillen ZP, Jericó D, Fontanellas A, Trocóniz IF. Mechanistic modelling of enzyme-restoration effects for new recombinant liver-targeted proteins in acute intermittent porphyria. Br J Pharmacol 2022; 179:3815-3830. [PMID: 35170015 PMCID: PMC9310908 DOI: 10.1111/bph.15821] [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] [Received: 10/25/2021] [Revised: 01/18/2022] [Accepted: 02/08/2022] [Indexed: 11/28/2022] Open
Abstract
Background and Purpose Acute intermittent porphyria (AIP) is a rare disease caused by a genetic mutation in the hepatic activity of the porphobilinogen‐deaminase. We aimed to develop a mechanistic model of the enzymatic restoration effects of a novel therapy based on the administration of different formulations of recombinant human‐PBGD (rhPBGD) linked to the ApoAI lipoprotein. This fusion protein circulates in blood, incorporating into HDL and penetrating hepatocytes. Experimental Approach Single i.v. dose of different formulations of rhPBGD linked to ApoAI were administered to AIP mice in which a porphyric attack was triggered by i.p. phenobarbital. Data consist on 24 h urine excreted amounts of heme precursors, 5‐aminolevulinic acid (ALA), PBG and total porphyrins that were analysed using non‐linear mixed‐effects analysis. Key Results The mechanistic model successfully characterized over time the amounts excreted in urine of the three heme precursors for different formulations of rhPBGD and unravelled several mechanisms in the heme pathway, such as the regulation in ALA synthesis by heme. Treatment with rhPBGD formulations restored PBGD activity, increasing up to 51 times the value of the rate of tPOR formation estimated from baseline. Model‐based simulations showed that several formulation prototypes provided efficient protective effects when administered up to 1 week prior to the occurrence of the AIP attack. Conclusion and Implications The model developed had excellent performance over a range of doses and formulation type. This mechanistic model warrants use beyond ApoAI‐conjugates and represents a useful tool towards more efficient drug treatments of other enzymopenias as well as for acute intermittent porphyria.
Collapse
Affiliation(s)
- Diego Vera-Yunca
- Pharmacometrics & Systems Pharmacology, Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain.,IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
| | - Karol M Córdoba
- IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.,Hepatology Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
| | - Zinnia P Parra-Guillen
- Pharmacometrics & Systems Pharmacology, Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain.,IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
| | - Daniel Jericó
- IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.,Hepatology Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
| | - Antonio Fontanellas
- IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.,Hepatology Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Iñaki F Trocóniz
- Pharmacometrics & Systems Pharmacology, Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain.,IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
| |
Collapse
|
|
46
|
Lee MJ, Lee I, Wang K. Recent Advances in RNA Therapy and Its Carriers to Treat the Single-Gene Neurological Disorders. Biomedicines 2022; 10:biomedicines10010158. [PMID: 35052837 PMCID: PMC8773368 DOI: 10.3390/biomedicines10010158] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 01/07/2022] [Accepted: 01/11/2022] [Indexed: 02/07/2023] Open
Abstract
The development of new sequencing technologies in the post-genomic era has accelerated the identification of causative mutations of several single gene disorders. Advances in cell and animal models provide insights into the underlining pathogenesis, which facilitates the development and maturation of new treatment strategies. The progress in biochemistry and molecular biology has established a new class of therapeutics—the short RNAs and expressible long RNAs. The sequences of therapeutic RNAs can be optimized to enhance their stability and translatability with reduced immunogenicity. The chemically-modified RNAs can also increase their stability during intracellular trafficking. In addition, the development of safe and high efficiency carriers that preserves the integrity of therapeutic RNA molecules also accelerates the transition of RNA therapeutics into the clinic. For example, for diseases that are caused by genetic defects in a specific protein, an effective approach termed “protein replacement therapy” can provide treatment through the delivery of modified translatable mRNAs. Short interference RNAs can also be used to treat diseases caused by gain of function mutations or restore the splicing aberration defects. Here we review the applications of newly developed RNA-based therapeutics and its delivery and discuss the clinical evidence supporting the potential of RNA-based therapy in single-gene neurological disorders.
Collapse
Affiliation(s)
- Ming-Jen Lee
- Department of Neurology, National Taiwan University Hospital, Taipei 10012, Taiwan;
- Department of Medical Genetics, National Taiwan University Hospital, Taipei 10012, Taiwan
| | - Inyoul Lee
- Institute for Systems Biology, Seattle, WA 98109, USA;
| | - Kai Wang
- Institute for Systems Biology, Seattle, WA 98109, USA;
- Correspondence: ; Tel.: +1-206-732-1336
| |
Collapse
|
|
47
|
Córdoba KM, Serrano-Mendioroz I, Jericó D, Merino M, Jiang L, Sampedro A, Alegre M, Corrales F, Garrido MJ, Martini PGV, Lanciego JL, Prieto J, Berraondo P, Fontanellas A. Recombinant porphobilinogen deaminase targeted to the liver corrects enzymopenia in a mouse model of acute intermittent porphyria. Sci Transl Med 2022; 14:eabc0700. [PMID: 35020410 DOI: 10.1126/scitranslmed.abc0700] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Correction of enzymatic deficits in hepatocytes by systemic administration of a recombinant protein is a desired therapeutic goal for hepatic enzymopenic disorders such as acute intermittent porphyria (AIP), an inherited porphobilinogen deaminase (PBGD) deficiency. Apolipoprotein A-I (ApoAI) is internalized into hepatocytes during the centripetal transport of cholesterol. Here, we generated a recombinant protein formed by linking ApoAI to the amino terminus of human PBGD (rhApoAI-PBGD) in an attempt to transfer PBGD into liver cells. In vivo experiments showed that, after intravenous injection, rhApoAI-PBGD circulates in blood incorporated into high-density lipoprotein (HDL), penetrates into hepatocytes, and crosses the blood-brain barrier, increasing PBGD activity in both the liver and brain. Consistently, the intravenous administration of rhApoAI-PBGD or the hyperfunctional rApoAI-PBGD-I129M/N340S (rApoAI-PBGDms) variant efficiently prevented and abrogated phenobarbital-induced acute attacks in a mouse model of AIP. One month after a single intravenous dose of rApoAI-PBGDms, the protein was still detectable in the liver, and hepatic PBGD activity remained increased above control values. A long-lasting therapeutic effect of rApoAI-PBGDms was observed after either intravenous or subcutaneous administration. These data describe a method to deliver PBGD to hepatocytes with resulting enhanced hepatic enzymatic activity and protection against AIP attacks in rodent models, suggesting that the approach might be an effective therapy for AIP.
Collapse
Affiliation(s)
- Karol M Córdoba
- Hepatology Program, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), 31008 Pamplona, Spain
| | - Irantzu Serrano-Mendioroz
- Hepatology Program, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), 31008 Pamplona, Spain
| | - Daniel Jericó
- Hepatology Program, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), 31008 Pamplona, Spain
| | - María Merino
- Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, 31008 Pamplona, Spain
| | - Lei Jiang
- Moderna Inc., Cambridge, MA 02139, USA
| | - Ana Sampedro
- Hepatology Program, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), 31008 Pamplona, Spain
| | - Manuel Alegre
- Neurophysiology Laboratory, Neuroscience Area, CIMA and Clínica Universitaria, University of Navarra, 31008 Pamplona, Spain
| | - Fernando Corrales
- Proteomics Unit, Centro Nacional de Biotecnología (CSIC), 28049 Madrid, Spain
| | - María J Garrido
- Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, 31008 Pamplona, Spain
| | | | - José Luis Lanciego
- Navarra Institute for Health Research (IDISNA), 31008 Pamplona, Spain
- Neurosciences Department, CIMA-University of Navarra, 31008 Pamplona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNed), Instituto de Salud Carlos III, 28031 Madrid, Spain
| | - Jesús Prieto
- Hepatology Program, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain
| | - Pedro Berraondo
- Navarra Institute for Health Research (IDISNA), 31008 Pamplona, Spain
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, 31008 Pamplona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Antonio Fontanellas
- Hepatology Program, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), 31008 Pamplona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
| |
Collapse
|
|
48
|
Matsuda H, Ito H, Nukaga Y, Uehara S, Sato K, Hara RI, Wada T. Solid-phase synthesis of oligouridine boranophosphates using the H-boranophosphonate method with 2′-O-(2-cyanoethoxymethyl) protection. Tetrahedron Lett 2021. [DOI: 10.1016/j.tetlet.2021.153526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
|
|
49
|
Rinoldi C, Zargarian SS, Nakielski P, Li X, Liguori A, Petronella F, Presutti D, Wang Q, Costantini M, De Sio L, Gualandi C, Ding B, Pierini F. Nanotechnology-Assisted RNA Delivery: From Nucleic Acid Therapeutics to COVID-19 Vaccines. SMALL METHODS 2021; 5:e2100402. [PMID: 34514087 PMCID: PMC8420172 DOI: 10.1002/smtd.202100402] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 07/04/2021] [Indexed: 05/07/2023]
Abstract
In recent years, the main quest of science has been the pioneering of the groundbreaking biomedical strategies needed for achieving a personalized medicine. Ribonucleic acids (RNAs) are outstanding bioactive macromolecules identified as pivotal actors in regulating a wide range of biochemical pathways. The ability to intimately control the cell fate and tissue activities makes RNA-based drugs the most fascinating family of bioactive agents. However, achieving a widespread application of RNA therapeutics in humans is still a challenging feat, due to both the instability of naked RNA and the presence of biological barriers aimed at hindering the entrance of RNA into cells. Recently, material scientists' enormous efforts have led to the development of various classes of nanostructured carriers customized to overcome these limitations. This work systematically reviews the current advances in developing the next generation of drugs based on nanotechnology-assisted RNA delivery. The features of the most used RNA molecules are presented, together with the development strategies and properties of nanostructured vehicles. Also provided is an in-depth overview of various therapeutic applications of the presented systems, including coronavirus disease vaccines and the newest trends in the field. Lastly, emerging challenges and future perspectives for nanotechnology-mediated RNA therapies are discussed.
Collapse
Affiliation(s)
- Chiara Rinoldi
- Department of Biosystems and Soft MatterInstitute of Fundamental Technological ResearchPolish Academy of Sciencesul. Pawińskiego 5BWarsaw02‐106Poland
| | - Seyed Shahrooz Zargarian
- Department of Biosystems and Soft MatterInstitute of Fundamental Technological ResearchPolish Academy of Sciencesul. Pawińskiego 5BWarsaw02‐106Poland
| | - Pawel Nakielski
- Department of Biosystems and Soft MatterInstitute of Fundamental Technological ResearchPolish Academy of Sciencesul. Pawińskiego 5BWarsaw02‐106Poland
| | - Xiaoran Li
- Innovation Center for Textile Science and TechnologyDonghua UniversityWest Yan'an Road 1882Shanghai200051China
| | - Anna Liguori
- Department of Chemistry “Giacomo Ciamician” and INSTM UdR of BolognaUniversity of BolognaVia Selmi 2Bologna40126Italy
| | - Francesca Petronella
- Institute of Crystallography CNR‐ICNational Research Council of ItalyVia Salaria Km 29.300Monterotondo – Rome00015Italy
| | - Dario Presutti
- Institute of Physical ChemistryPolish Academy of Sciencesul. M. Kasprzaka 44/52Warsaw01‐224Poland
| | - Qiusheng Wang
- Innovation Center for Textile Science and TechnologyDonghua UniversityWest Yan'an Road 1882Shanghai200051China
| | - Marco Costantini
- Institute of Physical ChemistryPolish Academy of Sciencesul. M. Kasprzaka 44/52Warsaw01‐224Poland
| | - Luciano De Sio
- Department of Medico‐Surgical Sciences and BiotechnologiesResearch Center for BiophotonicsSapienza University of RomeCorso della Repubblica 79Latina04100Italy
- CNR‐Lab. LicrylInstitute NANOTECArcavacata di Rende87036Italy
| | - Chiara Gualandi
- Department of Chemistry “Giacomo Ciamician” and INSTM UdR of BolognaUniversity of BolognaVia Selmi 2Bologna40126Italy
- Interdepartmental Center for Industrial Research on Advanced Applications in Mechanical Engineering and Materials TechnologyCIRI‐MAMUniversity of BolognaViale Risorgimento 2Bologna40136Italy
| | - Bin Ding
- Innovation Center for Textile Science and TechnologyDonghua UniversityWest Yan'an Road 1882Shanghai200051China
| | - Filippo Pierini
- Department of Biosystems and Soft MatterInstitute of Fundamental Technological ResearchPolish Academy of Sciencesul. Pawińskiego 5BWarsaw02‐106Poland
| |
Collapse
|