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Goyal A, Afzal M, Khan NH, Goyal K, Srinivasamurthy SK, Gupta G, Benod Kumar K, Ali H, Rana M, Wong LS, Kumarasamy V, Subramaniyan V. Targeting p53-p21 signaling to enhance mesenchymal stem cell regenerative potential. Regen Ther 2025; 29:352-363. [PMID: 40248767 PMCID: PMC12004386 DOI: 10.1016/j.reth.2025.03.007] [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: 01/26/2025] [Revised: 03/09/2025] [Accepted: 03/18/2025] [Indexed: 04/19/2025] Open
Abstract
Mesenchymal stem cells (MSCs) are properties of self-renewal and differentiation potentials and thus are very appealing to regenerative medicine. Nevertheless, their therapeutic potential is frequently constrained by senescence, limited proliferation, and stress-induced apoptosis. The key role of the p53-p21 biology in MSC biology resides in safeguarding genomic stability while promoting senescence and limiting regenerative capacity upon over-activation demonstrated. This pathway is a key point for improving MSC function and exploiting the inherent limitations. Recent advances indicate that senescence can be delayed by targeting the p53-p21 signaling and improved MSC proliferation and differentiation capacity. PFT-α pharmacological agents transiently inhibit p53 from increasing proliferation and lineage-specific differentiation, while antioxidants such as hydrogen-rich saline and epigallocatechin 3 gallate (EGCG) suppress oxidative stress and attenuate p53 p21 signaling. Genetic tools like CRISPR-Cas9 and RNA interference also precisely modulate TP53 and CDKN1A expression to optimize MSC functionality. The interplay of p53-p21 with pathways like Wnt/β-catenin and MAPK further highlights opportunities for combinatorial therapies to enhance MSC resilience and regenerative outcomes. This review aims to offer a holistic view of how p53-p21 targeting can further the regenerative potential of MSCs, resolving senescence, proliferation, and stress resilience towards advanced therapeutics built on MSCs.
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Affiliation(s)
- Ahsas Goyal
- Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, India
| | - Muhammad Afzal
- Department of Pharmaceutical Sciences, Pharmacy Program, Batterjee Medical College, P.O. Box 6231, Jeddah 21442, Saudi Arabia
| | - Nawaid Hussain Khan
- Faculty of Medicine, Ala-Too International University, Bishkek, Kyrgyz Republic
| | - Kavita Goyal
- Department of Biotechnology, Graphic Era (Deemed to be University), Clement Town, Dehradun 248002, India
| | - Suresh Kumar Srinivasamurthy
- Department of Pharmacology, Ras Al Khaimah College of Medical Sciences, Ras Al Khaimah Medical & Health Sciences University, P.O. Box 11172, Ras Al Khaimah, United Arab Emirates
| | - Gaurav Gupta
- Centre for Research Impact & Outcome, Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab 140401, India
- Centre of Medical and Bio-allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates
| | - K. Benod Kumar
- Department of General Surgery, Consultant Head and Neck Surgical Oncology, Dr.D.Y.Patil Medical College, Hospital and Research Centre, Pimpri, Pune, India
| | - Haider Ali
- Centre for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
| | - Mohit Rana
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
| | - Ling Shing Wong
- Faculty of Health and Life Sciences, INTI International University, Nilai 71800, Malaysia
| | - Vinoth Kumarasamy
- Department of Parasitology and Medical Entomology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Cheras, 56000, Kuala Lumpur, Malaysia
| | - Vetriselvan Subramaniyan
- Division of Pharmacology, Faculty of Medical and Life Sciences, Sunway University, Bandar Sunway, 47500 Selangor Darul Ehsan, Malaysia
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Bhati V, Prasad S, Kabra A. RNA-based therapies for neurodegenerative disease: Targeting molecular mechanisms for disease modification. Mol Cell Neurosci 2025; 133:104010. [PMID: 40340000 DOI: 10.1016/j.mcn.2025.104010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2025] [Revised: 04/23/2025] [Accepted: 04/30/2025] [Indexed: 05/10/2025] Open
Abstract
Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) are characterized by progressive neuronal damage, protein aggregation, and chronic inflammation, leading to cognitive and motor impairments. Despite symptomatic relief from current therapies, disease-modifying treatments targeting the core molecular mechanism are still lacking. RNA-based therapies offer a promising approach to treating neurodegenerative disease by targeting molecular mechanisms such as gene expression, protein synthesis, and neuroinflammation. Therapeutic strategies include Long non-coding RNA (lncRNA), Antisense oligonucleotides (ASOs), RNA interference (RNAi), small interfering RNA (siRNA) and short hairpin RNA (shRNA), messenger RNA (mRNA) therapies, and microRNA (miRNA)-based interventions. These therapies aim to decrease toxic protein accumulation, restore deficient proteins, and modulate inflammatory responses in conditions like AD, PD, and HD. Unlike conventional treatments that primarily manage symptoms, RNA-based therapies have the potential to modify disease progression by addressing its root causes. This review aims to provide a comprehensive overview of current RNA-based therapeutic strategies for neurodegenerative diseases, discussing their mechanism of action, preclinical and clinical advancement. It further explores innovative solutions, including nanocarrier-mediated delivery, chemical modifications to enhance RNA stability, and personalized medicine approaches guided by genetic profiling that are being developed to overcome these barriers. This review also underscores the therapeutic opportunities and current limitations of RNA-based interventions, highlighting their potential to transform the future of neurodegenerative disease management.
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Affiliation(s)
- Vishal Bhati
- University Institute of Pharma Sciences, Chandigarh University, Mohali-140413, Punjab, India
| | - Sonima Prasad
- University Institute of Pharma Sciences, Chandigarh University, Mohali-140413, Punjab, India
| | - Atul Kabra
- University Institute of Pharma Sciences, Chandigarh University, Mohali-140413, Punjab, India.
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Deepali, Goel N, Khandnor P. DeepOmicsSurv: a deep learning-based model for survival prediction of oral cancer. Discov Oncol 2025; 16:614. [PMID: 40278990 PMCID: PMC12031713 DOI: 10.1007/s12672-025-02346-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Accepted: 04/09/2025] [Indexed: 04/26/2025] Open
Abstract
OBJECTIVE Oral cancer is an important health challenge worldwide and accurate survival time prediction of this disease can guide treatment decisions. This study aims to propose a deep learning-based model, DeepOmicsSurv, to predict survival in oral cancer patients using clinical and multi-omics data. METHODS DeepOmicsSurv builds on the DeepSurv model, incorporating multi-head attention convolutional layers, dropout, pooling, and batch normalization to boost its strength and precision. Various dimensionality reduction techniques, including Principal Component Analysis (PCA), Kernel PCA, Non-Negative Matrix Factorization (NMF), Singular Value Decomposition (SVD), Partial Least Squares (PLS), Multidimensional Scaling (MDS), and Autoencoders, were employed to manage the high-dimensional omics data. The model's performance was evaluated against DeepSurv, DeepHit, Cox Proportional Hazards (CoxPH), Convolutional Neural Networks (CNN), and Recurrent Neural Networks (RNN). Additionally, SHapley Additive Explanations (SHAP) was used to analyze the impact of clinical features on survival predictions. RESULTS DeepOmicsSurv achieved a C-index of 0.966, MSE of 0.0138, RMSE of 0.1174, MAE of 0.0795, and MedAE of 0.0515, outperforming other deep learning models. Among various dimensionality reduction techniques, autoencoder performed the best with DeepOmicsSurv. SHAP analysis showed that Age, AJCC N Stage, alcohol history and patient smoking history are prevalent clinical features for survival time. CONCLUSION In conclusion, DeepOmicsSurv has the potential to predict survival time in oral cancer patients. This model achieved high accuracy with various data types including Clinical, DNAmethylation + clinical, mRNA + clinical, Copy number alteration + clinical, or multi-omics data. Additionally, SHAP analysis reveals clinical factors that influence survival time.
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Affiliation(s)
- Deepali
- University Institute of Engineering and Technology, Panjab University, Chandigarh, 160014, India
- Department of Computer Science, Guru Nanak College, Budhlada, 151502, India
| | - Neelam Goel
- University Institute of Engineering and Technology, Panjab University, Chandigarh, 160014, India.
| | - Padmavati Khandnor
- Department of Computer Science, Punjab Engineering College (Deemed to be University), Chandigarh, 160012, India
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Oghenemaro EF, Khaleel AQ, Rizaev JA, Roopashree R, Suliman M, Kazmi SW, Hjazi A, Rajput P, Mustafa YF, Abosaoda MK. Dysregulation of GAS5-miRNA-Mediated Signaling Pathways in Cancer Pathobiology: A Comprehensive Exploration of Pathways Influenced by this Axis. Biochem Genet 2025; 63:1149-1175. [PMID: 39718723 DOI: 10.1007/s10528-024-10997-x] [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: 09/30/2024] [Accepted: 12/04/2024] [Indexed: 12/25/2024]
Abstract
The long non-coding RNA Growth Arrest-Specific 5 (GAS5) is pivotal in modulating key signaling pathways by functioning as a molecular sponge for microRNAs (miRNAs). GAS5 is notably recognized for its antitumor properties, primarily through its ability to sequester oncogenic miRNAs, thereby influencing critical pathways such as p53, Wnt/β-catenin, and PI3K/Akt, all of which are integral to cell proliferation, apoptosis, and metastasis. The disruption of GAS5-miRNA interactions has been implicated in various malignancies, reinforcing its potential as both a biomarker and a therapeutic target. This paper delves into the intricate signaling cascades affected by GAS5-miRNA interactions and thoroughly investigates the diagnosis and treatment prospects associated with GAS5. Moreover, it addresses both the challenges and opportunities for translational applicability of these findings in clinical environments. The study emphasizes GAS5's significance within the cancer molecular landscape and posits that precise modulation of GAS5-miRNA interactions could catalyze transformative developments in cancer diagnostics and therapeutic approaches. This comprehensive review not only highlights the critical role of non-coding RNAs in cancer biology but also aims to lay the groundwork for future investigations aimed at harnessing these insights for therapeutic interventions.
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Affiliation(s)
- Enwa Felix Oghenemaro
- Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Delta State University, Abraka, Delta State, Nigeria
| | - Abdulrahman Qais Khaleel
- Department of Medical Instruments Engineering, College of Engineering, University of Al Maarif, Al Anbar, 31001, Iraq.
| | - Jasur Alimdjanovich Rizaev
- Department of Public Health and Healthcare Management, Rector, Samarkand State Medical University, 18, Amir Temur Street, Samarkand, Uzbekistan
| | - R Roopashree
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
| | - Muath Suliman
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | - Syeda Wajida Kazmi
- Chandigarh Pharmacy College, Chandigarh Group of Colleges, Jhanjeri, Mohali, 140307, Punjab, India
| | - Ahmed Hjazi
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam Bin Abdulaziz University, 11942, Al-Kharj, Saudi Arabia.
| | - Pranchal Rajput
- Uttaranchal Institute of Pharmaceutical Sciences, Division of Research and Innovation, Uttaranchal University, Dehradun, India
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, 41001, Iraq
| | - Munther Kadhim Abosaoda
- College of Pharmacy, The Islamic University, Najaf, Iraq
- Department of Medical Analysis, Medical Laboratory Technique College, The Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- Department of Medical Analysis, Medical Laboratory Technique College, The Islamic University of Babylon, Babylon, Iraq
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Abbasi M, Aghamollaei H, Vaez A, Amani AM, Kamyab H, Chelliapan S, Jamalpour S, Zambrano-Dávila R. Bringing ophthalmology into the scientific world: Novel nanoparticle-based strategies for ocular drug delivery. Ocul Surf 2025; 37:140-172. [PMID: 40147816 DOI: 10.1016/j.jtos.2025.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2025] [Revised: 03/03/2025] [Accepted: 03/21/2025] [Indexed: 03/29/2025]
Abstract
The distinctive benefits and drawbacks of various drug delivery strategies to supply corneal tissue improvement for sense organs have been the attention of studies worldwide in recent decades. Static and dynamic barriers of ocular tissue prevent foreign chemicals from entering and inhibit the active absorption of therapeutic medicines. The distribution of different medications to ocular tissue is one of the most appealing and demanding tasks for investigators in pharmacology, biomaterials, and ophthalmology, and it is critical for cornea wound healing due to the controlled release rate and increased drug bioavailability. It should be mentioned that the transport of various types of medications into the different sections of the eye, particularly the cornea, is exceedingly challenging because of its distinctive structure and various barriers throughout the eye. Nanoparticles are being studied to improve medicine delivery strategies for ocular disease. Repetitive corneal drug delivery using biodegradable nanocarriers allows a medicine to remain in different parts of the cornea for extended periods of time and thus improve administration route effectiveness. In this review, we discussed eye anatomy, ocular delivery barriers, as well as the emphasis on the biodegradable nanomaterials ranging from organic nanostructures, such as nanomicelles, polymers, liposomes, niosomes, nanowafers, nanoemulsions, nanosuspensions, nanocrystals, cubosomes, olaminosomes, hybridized NPs, dendrimers, bilosomes, solid lipid NPs, nanostructured lipid carriers, and nanofiber to organic nanomaterials like silver, gold, and mesoporous silica nanoparticles. In addition, we describe the nanotechnology-based ophthalmic medications that are presently on the market or in clinical studies. Finally, drawing on current trends and therapeutic approaches, we discuss the challenges that innovative optical drug delivery systems confront and propose future research routes. We hope that this review will serve as a source of motivation and inspiration for developing innovative ophthalmic formulations.
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Affiliation(s)
- Milad Abbasi
- Chemical Injuries Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Hossein Aghamollaei
- Chemical Injuries Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.
| | - Ahmad Vaez
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ali Mohammad Amani
- Department of Medical Nanotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Hesam Kamyab
- Department of Biomaterials, Saveetha Dental College and Hospital, Saveetha Institute of Medical and Technical Sciences, Chennai, 600077, India; The KU-KIST Graduate School of Energy and Environment, Korea University, 145 Anam-Ro, Seongbuk-Gu, Seoul, 02841, Republic of Korea; Universidad UTE, Quito, 170527, Ecuador.
| | - Shreeshivadasan Chelliapan
- Department of Smart Engineering and Advanced Technology, Faculty of Artificial Intelligence, Universiti Teknologi Malaysia, Jalan Sultan Yahya Petra, 54100, Kuala Lumpur, Malaysia.
| | - Sajad Jamalpour
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, 50603, Malaysia
| | - Renato Zambrano-Dávila
- Universidad UTE, Centro de Investigación en Salud Públicay Epidemiología Clínica (CISPEC), Quito, 170527, Ecuador
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Davies JWA, Bredy TW, Marshall PR. Cutting-edge RNA technologies to advance the understanding of learning and memory. Neurobiol Learn Mem 2025; 219:108050. [PMID: 40147812 DOI: 10.1016/j.nlm.2025.108050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Revised: 02/13/2025] [Accepted: 03/24/2025] [Indexed: 03/29/2025]
Abstract
Following the recent emergence of RNA as a therapeutic tool, and coupled with an explosion in the development of new RNA technologies, it is rapidly becoming clear that the 21st century is the era of RNA. Neuroscience as a discipline has a long history of embracing new technology to advance the understanding of brain function, particularly in the context of learning and memory. In this short review, we highlight four broad categories of emerging RNA technologies, namely: imaging, isolation, identification and manipulation, and discuss their potential to advance the fundamental understanding of how RNA impacts experience-dependent plasticity, learning, and memory.
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Affiliation(s)
- Joshua William Ashley Davies
- UQ Centre for RNA in Neuroscience, Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia; Genomic Plasticity Laboratory, Genome Sciences and Cancer Division & Eccles Institute of Neuroscience, John Curtain School of Medical Research, Australian National University, Canberra 2601, Australia.
| | - Timothy William Bredy
- UQ Centre for RNA in Neuroscience, Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia.
| | - Paul Robert Marshall
- Genomic Plasticity Laboratory, Genome Sciences and Cancer Division & Eccles Institute of Neuroscience, John Curtain School of Medical Research, Australian National University, Canberra 2601, Australia.
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Ang SP, Chia JE, Mukherjee D. Emerging, novel gene-modulating therapies for transthyretin amyloid cardiomyopathy. Heart Fail Rev 2025:10.1007/s10741-025-10502-5. [PMID: 40056371 DOI: 10.1007/s10741-025-10502-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/24/2025] [Indexed: 03/10/2025]
Abstract
Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive, life-threatening disease caused by the pathological deposition of misfolded transthyretin (TTR) protein in the myocardium, leading to restrictive cardiomyopathy and heart failure. While TTR stabilizers such as tafamidis and acoramidis are the only FDA-approved treatments, novel gene-modulating therapies are emerging as transformative approaches. Small interfering RNA (siRNA) and antisense oligonucleotide (ASO) therapies effectively reduce TTR production and have demonstrated promising clinical outcomes, though their use in cardiac amyloidosis remains investigational. CRISPR-Cas9 therapies represent a paradigm shift, offering a potential one-time treatment by permanently silencing the TTR gene. Recent clinical trials have shown significant TTR reduction and stabilization of disease biomarkers, although long-term safety and efficacy require further evaluation. Despite the lack of direct comparisons among these modalities, their emergence highlights a promising future for ATTR-CM management. This review discusses the pathogenesis of ATTR-CM, mechanisms of novel gene-modulating therapies, clinical evidence, challenges, and the future outlook for advancing treatment options.
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Affiliation(s)
- Song Peng Ang
- Department of Medicine, Rutgers Health/Community Medical Center, Toms River, NJ, USA.
| | - Jia Ee Chia
- Department of Medicine, Texas Tech University Health Science Center, El Paso, TX, USA
| | - Debabrata Mukherjee
- Department of Medicine, Texas Tech University Health Science Center, El Paso, TX, USA
- Department of Cardiovascular Medicine, Texas Tech University Health Science Center, El Paso, TX, USA
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Ji Q, Kowalski KP, Golenberg EM, Chung SH, Barker ND, Bickford WA, Gong P. Cell-Penetrating Peptide-Mediated Delivery of Gene-Silencing Nucleic Acids to the Invasive Common Reed Phragmites australis via Foliar Application. PLANTS (BASEL, SWITZERLAND) 2025; 14:458. [PMID: 39943020 PMCID: PMC11820330 DOI: 10.3390/plants14030458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 01/18/2025] [Accepted: 01/21/2025] [Indexed: 02/16/2025]
Abstract
As a popular tool for gene function characterization and gene therapy, RNA interference (RNAi)-based gene silencing has been increasingly explored for potential applications to control invasive species. At least two major hurdles exist when applying this approach to invasive plants: (1) the design and screening of species- and gene-specific biomacromolecules (i.e., gene-silencing agents or GSAs) made of DNA, RNA, or peptides that can suppress the expression of target genes efficiently, and (2) the delivery vehicle needed to penetrate plant cell walls and other physical barriers (e.g., leaf cuticles). In this study, we investigated the cell-penetrating peptide (CPP)-mediated delivery of multiple types of GSAs (e.g., double-stranded RNA (dsRNA), artificial microRNA (amiRNA), and antisense oligonucleotide (ASO)) to knock down a putative phytoene desaturase (PDS) gene in the invasive common reed (Phragmites australis spp. australis). Both microscopic and quantitative gene expression evidence demonstrated the CPP-mediated internalization of GSA cargos and transient suppression of PDS expression in both treated and systemic leaves up to 7 days post foliar application. Although various GSA combinations and application rates and frequencies were tested, we observed limitations, including low gene-silencing efficiency and a lack of physiological trait alteration, likely owing to low CPP payload capacity and the incomplete characterization of the PDS-coding genes (e.g., the recent discovery of two PDS paralogs) in P. australis. Our work lays a foundation to support further research toward the development of convenient, cost-effective, field-deployable, and environmentally benign gene-silencing technologies for invasive P. australis management.
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Affiliation(s)
- Qing Ji
- Bennett Aerospace, Inc., Raleigh, NC 27603, USA;
| | - Kurt P. Kowalski
- U.S. Geological Survey, Great Lakes Science Center, Ann Arbor, MI 48105, USA; (K.P.K.); (W.A.B.)
| | - Edward M. Golenberg
- Department of Biological Sciences, Wayne State University, Detroit, MI 48201, USA;
| | - Seung Ho Chung
- Environmental Laboratory, U.S. Army Engineer Research and Development Center, Vicksburg, MS 39180, USA; (S.H.C.); (N.D.B.)
| | - Natalie D. Barker
- Environmental Laboratory, U.S. Army Engineer Research and Development Center, Vicksburg, MS 39180, USA; (S.H.C.); (N.D.B.)
| | - Wesley A. Bickford
- U.S. Geological Survey, Great Lakes Science Center, Ann Arbor, MI 48105, USA; (K.P.K.); (W.A.B.)
| | - Ping Gong
- Environmental Laboratory, U.S. Army Engineer Research and Development Center, Vicksburg, MS 39180, USA; (S.H.C.); (N.D.B.)
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9
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Mallick R, Basak S, Chowdhury P, Bhowmik P, Das RK, Banerjee A, Paul S, Pathak S, Duttaroy AK. Targeting Cytokine-Mediated Inflammation in Brain Disorders: Developing New Treatment Strategies. Pharmaceuticals (Basel) 2025; 18:104. [PMID: 39861166 PMCID: PMC11769149 DOI: 10.3390/ph18010104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 12/26/2024] [Accepted: 01/12/2025] [Indexed: 01/27/2025] Open
Abstract
Cytokine-mediated inflammation is increasingly recognized for playing a vital role in the pathophysiology of a wide range of brain disorders, including neurodegenerative, psychiatric, and neurodevelopmental problems. Pro-inflammatory cytokines such as interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) cause neuroinflammation, alter brain function, and accelerate disease development. Despite progress in understanding these pathways, effective medicines targeting brain inflammation are still limited. Traditional anti-inflammatory and immunomodulatory drugs are effective in peripheral inflammatory illnesses. Still, they face substantial hurdles when applied to the central nervous system (CNS), such as the blood-brain barrier (BBB) and unwanted systemic effects. This review highlights the developing treatment techniques for modifying cytokine-driven neuroinflammation, focusing on advances that selectively target critical cytokines involved in brain pathology. Novel approaches, including cytokine-specific inhibitors, antibody-based therapeutics, gene- and RNA-based interventions, and sophisticated drug delivery systems like nanoparticles, show promise with respect to lowering neuroinflammation with greater specificity and safety. Furthermore, developments in biomarker discoveries and neuroimaging techniques are improving our ability to monitor inflammatory responses, allowing for more accurate and personalized treatment regimens. Preclinical and clinical trial data demonstrate the therapeutic potential of these tailored techniques. However, significant challenges remain, such as improving delivery across the BBB and reducing off-target effects. As research advances, the creation of personalized, cytokine-centered therapeutics has the potential to alter the therapy landscape for brain illnesses, giving patients hope for better results and a higher quality of life.
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Affiliation(s)
- Rahul Mallick
- A.I. Virtanen Institute for Molecular Sciences, Faculty of Health Sciences, University of Eastern Finland, 70211 Kuopio, Finland;
| | - Sanjay Basak
- Molecular Biology Division, ICMR-National Institute of Nutrition, Indian Council of Medical Research, Hyderabad 500007, India;
| | - Premanjali Chowdhury
- Institute of Public Health and Clinical Nutrition, School of Medicine, Faculty of Health Sciences, University of Eastern Finland, 70210 Kuopio, Finland;
| | - Prasenjit Bhowmik
- Department of Chemistry, Uppsala Biomedical Centre, Uppsala University, SE-751 23 Uppsala, Sweden;
- Department of Textile Engineering, Green University of Bangladesh, Narayanganj 1461, Bangladesh
| | - Ranjit K. Das
- Department of Health and Biomedical Sciences, University of Texas Rio Grande Valley, Brownsville, TX 78520, USA;
| | - Antara Banerjee
- Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute (CHRI), Chettinad Academy of Research and Education (CARE), Chennai 603103, India; (A.B.); (S.P.)
| | - Sujay Paul
- School of Engineering and Sciences, Tecnologico de Monterrey, Queretaro 76130, Mexico;
| | - Surajit Pathak
- Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute (CHRI), Chettinad Academy of Research and Education (CARE), Chennai 603103, India; (A.B.); (S.P.)
| | - Asim K. Duttaroy
- Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, 0317 Oslo, Norway
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Hu J, Miao X, Yu LH. Long Non-Coding RNAs in Diabetic Cardiomyopathy: Potential Function as Biomarkers and Therapeutic Targets of Exercise Training. J Cardiovasc Transl Res 2025:10.1007/s12265-024-10586-8. [PMID: 39786669 DOI: 10.1007/s12265-024-10586-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Accepted: 12/28/2024] [Indexed: 01/12/2025]
Abstract
Recent studies emphasize the beneficial effects of exercise on diabetic cardiomyopathy (DCM), adding to the growing body of evidence that underscores the role of exercise in improving health outcomes. Despite this, a notable gap persists in the number of healthcare providers who actively prescribe exercise as a therapeutic intervention for DCM management. In addition, exercise modulates the expression of lncRNAs, which play a pivotal role in DCM progression. Further investigation into this relationship may facilitate the identification of novel biomarkers and therapeutic targets for DCM. This review consolidates recent advances in identifying lncRNAs biomarkers in DCM, summarizing the current knowledge on dysregulated lncRNAs and their molecular mechanisms. Additionally, it offers new insights into the mechanistic roles of lncRNAs, highlighting their potential as biomarkers and therapeutic targets for DCM. Overall, this review aims to inform future research and reinforce the significance of addressing diabetes-related cardiovascular diseases to potentially improve clinical outcomes.
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Affiliation(s)
- Jie Hu
- GuangZhou Sport University, 1268 Guangzhou Dadao Middle, Tianhe District, Guangzhou City, Guangdong Province, China
| | - Xinwen Miao
- Weihai Municipal Hospital Affiliated to Shandong University, No.70 Heping RoadHuancui District, Weihai, Shandong Province, China
| | - Li-Hua Yu
- College of Sports, YanShan University, No.438, West Hebei Street, Qinhuangdao City, Hebei Province, China.
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Nedaeinia R, Ranjbar M, Goli M, Etebari M, Safabakhsh S, Bayram H, Ferns GA, Tehrani HM, Salehi R. Medicinal Chemistry of Antisense Oligonucleotides for Therapeutic Use in SARS-CoV-2: Design Strategies and Challenges for Targeted Delivery. Curr Med Chem 2025; 32:1144-1167. [PMID: 38860908 DOI: 10.2174/0109298673300236240529195835] [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: 02/04/2024] [Revised: 04/16/2024] [Accepted: 04/19/2024] [Indexed: 06/12/2024]
Abstract
BACKGROUND The evolution of novel Severe Acute Respiratory Syndrome-related Coronavirus 2 (SARS-CoV-2) strains with greater degrees of infectivity, resistance to vaccine-induced acquired immunity, and more severe morbidity have contributed to the recent spread of COVID-19. In light of this, novel therapeutic alternatives with improved effectiveness and fewer side effects have become a necessity. Despite many new or repurposed antiviral agents recommended for Coronavirus disease (COVID-19) therapy, this objective remains unfulfilled. Under these circumstances, the scientific community holds the significant responsibility to develop classes of novel therapeutic modalities to combat SARS-CoV-2 with the least harmful side effects. OBJECTIVE Antisense Oligonucleotides (ASOs) are short single-stranded oligonucleotides that allow the specific targeting of RNA, leading to its degradation. They may also prevent cellular factors or machinery from binding to the target RNA. It is possible to improve the pharmacokinetics and pharmacodynamics of ASOs by chemical modification or bioconjugation, which may provide conditions for customization of a particular clinical target. This study aimed to outline the potential use of ASOs in the treatment of COVID-19 disease, along with the use of antisense stabilization and transfer methods, as well as future challenges and limitations. METHODS We have reviewed the structure and properties of ASOs containing nucleobase, sugar, or backbone modifications, and provided an overview of the therapeutic potential, delivery challenges, and strategies of ASOs in the treatment of COVID-19. RESULTS The first-line therapy for COVID-19-infected individuals, as well as the development of oligonucleotide- based drugs, warrants further investigation. Chemical changes in the oligonucleotide structure can affect the biological processes. These chemical alterations may lead to enhanced potency, while changing the pharmacokinetics and pharmacodynamics. CONCLUSION ASOs can be designed to target both coding and non-coding regions of the viral genome to disrupt or completely degrade the genomic RNA and thereby eliminate SARS-CoV-2. They may be very effective in areas, where vaccine distribution is challenging, and they may be helpful for future coronavirus pandemics.
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Affiliation(s)
- Reza Nedaeinia
- Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Maryam Ranjbar
- Department of Materials Engineering, Advanced Materials Research Center, Islamic Azad University, Najafabad Branch, Najafabad, Iran
- Vice Chancellery for Food and Drug, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mohammad Goli
- Department of Food Science and Technology, Laser and Biophotonics in Biotechnologies Research Center, Islamic Azad University, Isfahan (Khorasgan) Branch, Isfahan, Iran
| | - Mahmoud Etebari
- Department of Pharmacology and Toxicology, Isfahan Pharmaceutical Sciences Research Center, Faculty of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Saied Safabakhsh
- Micronesian Institute for Disease Prevention and Research, 736 Route 4, Suite 103, Sinajana, Guam, 96910, USA
| | - Hasan Bayram
- Koç University Research Centre for Translational Medicine (KUTTAM), School of Medicine, Koç University, Istanbul, Turkey
- Department of Pulmonary Medicine, School of Medicine, Koç University, Istanbul, Turkey
| | - Gordon A Ferns
- Department of Medical Education, Brighton and Sussex Medical School, Falmer, Brighton BN1 9PH, Sussex, UK
| | - Helena Moradiyan Tehrani
- Department of Food Science and Technology, Islamic Azad University, Damghan Branch, Semnan, Iran
| | - Rasoul Salehi
- Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
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Beigi A, Naghib SM, Matini A, Tajabadi M, Mozafari MR. Lipid-Based Nanocarriers for Targeted Gene Delivery in Lung Cancer Therapy: Exploring a Novel Therapeutic Paradigm. Curr Gene Ther 2025; 25:92-112. [PMID: 38778601 DOI: 10.2174/0115665232292768240503050508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 03/28/2024] [Accepted: 04/03/2024] [Indexed: 05/25/2024]
Abstract
Lung cancer is a significant cause of cancer-related death worldwide. It can be broadly categorised into small-cell lung cancer (SCLC) and Non-small cell lung cancer (NSCLC). Surgical intervention, radiation therapy, and the administration of chemotherapeutic medications are among the current treatment modalities. However, the application of chemotherapy may be limited in more advanced stages of metastasis due to the potential for adverse effects and a lack of cell selectivity. Although small-molecule anticancer treatments have demonstrated effectiveness, they still face several challenges. The challenges at hand in this context comprise insufficient solubility in water, limited bioavailability at specific sites, adverse effects, and the requirement for epidermal growth factor receptor inhibitors that are genetically tailored. Bio-macromolecular drugs, including small interfering RNA (siRNA) and messenger RNA (mRNA), are susceptible to degradation when exposed to the bodily fluids of humans, which can reduce stability and concentration. In this context, nanoscale delivery technologies are utilised. These agents offer encouraging prospects for the preservation and regulation of pharmaceutical substances, in addition to improving the solubility and stability of medications. Nanocarrier-based systems possess the notable advantage of facilitating accurate and sustained drug release, as opposed to traditional systemic methodologies. The primary focus of scientific investigation has been to augment the therapeutic efficacy of nanoparticles composed of lipids. Numerous nanoscale drug delivery techniques have been implemented to treat various respiratory ailments, such as lung cancer. These technologies have exhibited the potential to mitigate the limitations associated with conventional therapy. As an illustration, applying nanocarriers may enhance the solubility of small-molecule anticancer drugs and prevent the degradation of bio-macromolecular drugs. Furthermore, these devices can administer medications in a controlled and extended fashion, thereby augmenting the therapeutic intervention's effectiveness and reducing adverse reactions. However, despite these promising results, challenges remain that must be addressed. Multiple factors necessitate consideration when contemplating the application of nanoparticles in medical interventions. To begin with, the advancement of more efficient delivery methods is imperative. In addition, a comprehensive investigation into the potential toxicity of nanoparticles is required. Finally, additional research is needed to comprehend these treatments' enduring ramifications. Despite these challenges, the field of nanomedicine demonstrates considerable promise in enhancing the therapy of lung cancer and other respiratory diseases.
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Affiliation(s)
- Anahita Beigi
- Nanotechnology Department, School of Advanced Technologies, Iran University of Science and Technology, Tehran, Iran
| | - Seyed Morteza Naghib
- Nanotechnology Department, School of Advanced Technologies, Iran University of Science and Technology, Tehran, Iran
| | - Amir Matini
- Nanotechnology Department, School of Advanced Technologies, Iran University of Science and Technology, Tehran, Iran
| | - Maryam Tajabadi
- School of Metallurgy and Materials Engineering, Iran University of Science and Technology (IUST), Narmak, Tehran, 16844, Iran
| | - Mohammad Reza Mozafari
- Australasian Nanoscience and Nanotechnology Initiative (ANNI), Monash University LPO, Clayton, VIC 3168, Australia
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13
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Somerville EN, Gan-Or Z. Genetic-based diagnostics of Parkinson's disease and other Parkinsonian syndromes. Expert Rev Mol Diagn 2024:1-13. [PMID: 39545628 DOI: 10.1080/14737159.2024.2427625] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Accepted: 11/06/2024] [Indexed: 11/17/2024]
Abstract
INTRODUCTION Parkinson's disease (PD) is a complex disorder with vast clinical heterogeneity. Recent genetic, imaging and clinical evidence suggest that there are multiple subtypes of PD, and perhaps even distinct clinical entities, which are being diagnosed under the umbrella of PD. These might have similar clinical presentation, but potentially different underlying mechanisms, which, in future, will require different treatments. Despite extensive genetic research progress, genetic testing is still not a common practice in clinical patient care. AREAS COVERED This review examines the numerous genes that have been discovered to affect the risk of, or cause, PD. We also outline genetic variants that affect PD age at onset, its progression, and the presence or severity of motor and non-motor symptoms. We differentiate between PD, other synucleinopathies, and atypical parkinsonism syndromes, and describe genes responsible for familial forms of typical PD and atypical parkinsonism. Lastly, we present current clinical trails that are underway for targeted therapies, particularly for GBA1-PD and LRRK2-PD which are the most significant subtypes. EXPERT OPINION While genetic studies alone cannot be diagnostic for PD, proper utilization of genetic screening for PD could improve diagnostic accuracy and predictions for prognosis, guide treatment, and identify individuals that qualify for clinical trials.
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Affiliation(s)
- Emma N Somerville
- The Neuro (Montréal Neurological Institute-Hospital), McGill University, Montréal, Canada
- Department of Human Genetics, McGill University, Montréal, Canada
| | - Ziv Gan-Or
- The Neuro (Montréal Neurological Institute-Hospital), McGill University, Montréal, Canada
- Department of Human Genetics, McGill University, Montréal, Canada
- Department of Neurology and Neurosurgery, McGill University, Montréal, Canada
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14
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Masrour M, Khanmohammadi S, Habibzadeh A, Fallahtafti P. LncRNA MALAT1 as diagnostic and prognostic biomarker in colorectal cancers: A systematic review and meta-analysis. PLoS One 2024; 19:e0308009. [PMID: 39471147 PMCID: PMC11521308 DOI: 10.1371/journal.pone.0308009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Accepted: 07/16/2024] [Indexed: 11/01/2024] Open
Abstract
OBJECTIVE This study investigated the relationship between the long non-coding RNA Metastasis-Associated Lung Adenocarcinoma Transcript 1 (MALAT1) expression and colorectal cancer (CRC) using a thorough systematic review and meta-analysis. METHODS Under the PRISMA guidelines, a systematic review was conducted on studies published from the databases' inception to September 18, 2023. Prognostic value and diagnostic accuracy were explored. Additionally, the association between levels of MALAT1 expression and pathological features was investigated. The statistical analysis was performed using the "meta" package of R. RESULTS Among the pathological parameters examined, based on three studies involving 51 cases of metastatic CRC and 135 cases of non-metastatic CRC, a statistically significant correlation was found between the expression level of MALAT1 and distant metastasis, with an OR of 16.0118 (95% CI: 4.5618-56.2015). Three studies involving 378 cases reported overall survival and had a pooled HR of 2.3854 (95% CI: 1.3272-4.2875). Three studies involving 436 cases reported disease-free survival and had a pooled HR of 2.4772 (95% CI: 1.3774-4.4549). All prognosis studies utilized tumor tissue samples as specimens to assess the expression level of MALAT1. Case-to-control diagnostic studies with 126 cases and 126 controls had a pooled AUC value of 0.6173 (95% CI: 0.5436-0.6909), a pooled sensitivity of 0.675 (95% CI: 0.324-0.900), and a pooled specificity of 0.771 (95% CI: 0.685-0.839). CONCLUSIONS The expression of MALAT1 in CRC is highly correlated with distant metastasis and has an impact on survival and prognosis. MALAT1 could also be employed as a diagnostic biomarker. More prospective studies should be performed to assess the MALAT1 diagnostic potential in the early stages of CRC.
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Affiliation(s)
- Mahdi Masrour
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Shaghayegh Khanmohammadi
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Parisa Fallahtafti
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Tehran Heart Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
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15
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Hasturk B, Eren F. A therapeutic approach for the hepatitis C virus: in silico design of an antisense oligonucleotide-based candidate capsid inhibitor. Virus Genes 2024; 60:446-454. [PMID: 39083128 DOI: 10.1007/s11262-024-02088-1] [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: 03/19/2024] [Accepted: 06/30/2024] [Indexed: 09/10/2024]
Abstract
Direct-acting antiviral (DAA) drugs have been shown to effectively reduce viral load and cure a high proportion of hepatitis C virus (HCV) infections. However, costs associated with the course of therapy and any possible adverse effects should also be considered. It is important to acknowledge, moreover, that certain groups may not be eligible for treatment. Given that there is currently no approved vaccine for HCV infection, the need for an effective, safe, and accessible treatment remains a crucial priority. The aim of this study is to develop an antisense oligonucleotide (ASO)-based therapeutic drug that can inhibit HCV capsid. After analyzing 817 HCV capsid protein mRNA sequences using the NCBI Virus Data Portal, a conserved region of 7 nucleotides (nt) was identified in all genotypes (1-7). However, because of its high GC% content, this region is not a suitable target for ASO. Conversely, the other highly conserved region, which is only 8 nt long, was preserved in 801 datasets after removing missing and differing sequence data. The candidate ASO was then investigated using computer simulations to assess its potential. Thus, it is possible that the ASO sequence consisting of 8 nt could be a viable therapeutic target for the inhibition of HCV capsid. Furthermore, the 7 nt sequence, which is conserved in all datasets, may be targeted using alternative strategies in lieu of ASO-based targeting.
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Affiliation(s)
- Burcu Hasturk
- Department of Medical Biology and Genetics, Institute of Health Sciences, Marmara University, Istanbul, Turkey
| | - Fatih Eren
- Faculty of Medicine, Department of Medical Biology, Marmara University, Istanbul, Turkey.
- Institute of Gastroenterology, Liver Research Unit, Marmara University, Istanbul, Turkey.
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16
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Li J, Foged C. Evaluating the breadth of nucleic acid-based payloads delivered in lipid nanoparticles to establish fundamental differences in development. Expert Opin Drug Deliv 2024; 21:1441-1461. [PMID: 39387233 DOI: 10.1080/17425247.2024.2409142] [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: 03/19/2024] [Revised: 08/29/2024] [Accepted: 09/23/2024] [Indexed: 10/15/2024]
Abstract
INTRODUCTION Nucleic acid (NA)-based therapeutics have shown great potential for downregulating or augmenting gene expression, and for promising applications, e.g., protein-replacement therapy and vaccination, a comprehensive understanding of the requirements for their targeted delivery to specific tissues or cells is needed. AREAS COVERED In this review, we discuss clinical applications of four representative types of NA-based therapeutics, i.e. antisense oligonucleotides, small interfering RNA, messenger RNA, and circular RNA, with a focus on the lipid nanoparticle (LNP) technology used for intracellular delivery. The in vivo fate of LNPs is discussed to improve the understanding of trafficking of nanomedicines at the systemic and cellular levels. In addition, NA-based vaccines are discussed, focusing on targeting antigen-presenting cells and immune activation. EXPERT OPINION Optimization of delivery systems for NA-based therapeutics is mainly focused on the standard requirements of prolonged systemic circulation and enhancing endosomal escape. Depending on the final destination in specific target tissues or cells, strategies should be adjusted to achieve the desired biodistribution of NA-based payloads. More studies relating to the pharmacokinetics of both cargo and carrier are encouraged, because their in vivo fates may differ, considering the possibility of premature cargo release before reaching the target.
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Affiliation(s)
- Jinjin Li
- Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen Ø, Denmark
| | - Camilla Foged
- Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen Ø, Denmark
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17
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Chan CH, Pearce DA. Demystifying gene(tic) therapies. Eur J Med Genet 2024; 71:104963. [PMID: 39069254 DOI: 10.1016/j.ejmg.2024.104963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 06/24/2024] [Accepted: 07/25/2024] [Indexed: 07/30/2024]
Abstract
This article summarizes the discussion from a session entitled "Demystifying gene therapies" that was held at the joint RE(ACT) congress and IRDiRC conference, 14-15 March 2023 in Berlin, Germany. The focus of this session was to discuss the changing landscape of genetic therapies and whether current resources exist to provide adequate education to stakeholders, such as researchers, clinicians, patient advocates, legislators, as well as the patients and their families. The goal of this article is not to provide a comprehensive overview of the current landscape in genetic therapies, but rather to highlight resources that may be useful to help "demystify" the myriad of genetic therapeutic approaches.
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Affiliation(s)
| | - David A Pearce
- Sanford Research, Sioux Falls, SD, USA; Sanford Health, Sioux Falls, SD, USA; Dept. of Pediatrics, Sanford School of Medicine, University of South Dakota, USA.
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18
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Cochran M, Arias D, Burke R, Chu D, Erdogan G, Hood M, Kovach P, Kwon HW, Chen Y, Moon M, Miller CD, Huang H, Levin A, Doppalapudi VR. Structure-Activity Relationship of Antibody-Oligonucleotide Conjugates: Evaluating Bioconjugation Strategies for Antibody-siRNA Conjugates for Drug Development. J Med Chem 2024; 67:14852-14867. [PMID: 39197831 PMCID: PMC11403602 DOI: 10.1021/acs.jmedchem.4c00802] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/01/2024]
Abstract
Antibody-oligonucleotide conjugates are a promising class of therapeutics for extrahepatic delivery of small interfering ribonucleic acids (siRNAs). These conjugates can be optimized for improved delivery and mRNA knockdown (KD) through understanding of structure-activity relationships. In this study, we systematically examined factors including antibody isotype, siRNA chemistry, linkers, conjugation chemistry, PEGylation, and drug-to-antibody ratios (DARs) for their impact on bioconjugation, pharmacokinetics (PK), siRNA delivery, and bioactivity. Conjugation site (cysteine, lysine, and Asn297 glycan) and DAR proved critical for optimal conjugate PK and siRNA delivery. SiRNA chemistry including 2' sugar modifications and positioning of phosphorothioates were found to be critical for delivery and duration of action. By utilizing cleavable and noncleavable linkers, we demonstrated the impact of linkers on PK and mRNA KD. To achieve optimal properties of antibody-siRNA conjugates, a careful selection of siRNA chemistry, DAR, conjugation sites, linkers, and antibody isotype is necessary.
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Affiliation(s)
- Michael Cochran
- Avidity Biosciences, Inc., 10578 Science Center Drive Suite 125. San Diego, California 92121, United States
| | - Danny Arias
- Avidity Biosciences, Inc., 10578 Science Center Drive Suite 125. San Diego, California 92121, United States
| | - Rob Burke
- Avidity Biosciences, Inc., 10578 Science Center Drive Suite 125. San Diego, California 92121, United States
| | - David Chu
- Avidity Biosciences, Inc., 10578 Science Center Drive Suite 125. San Diego, California 92121, United States
| | - Gulin Erdogan
- Avidity Biosciences, Inc., 10578 Science Center Drive Suite 125. San Diego, California 92121, United States
| | - Michael Hood
- Avidity Biosciences, Inc., 10578 Science Center Drive Suite 125. San Diego, California 92121, United States
| | - Philip Kovach
- Avidity Biosciences, Inc., 10578 Science Center Drive Suite 125. San Diego, California 92121, United States
| | - Hae Won Kwon
- Avidity Biosciences, Inc., 10578 Science Center Drive Suite 125. San Diego, California 92121, United States
| | - Yanling Chen
- Avidity Biosciences, Inc., 10578 Science Center Drive Suite 125. San Diego, California 92121, United States
| | - Michael Moon
- Avidity Biosciences, Inc., 10578 Science Center Drive Suite 125. San Diego, California 92121, United States
| | - Christopher D Miller
- Avidity Biosciences, Inc., 10578 Science Center Drive Suite 125. San Diego, California 92121, United States
| | - Hanhua Huang
- Avidity Biosciences, Inc., 10578 Science Center Drive Suite 125. San Diego, California 92121, United States
| | - Arthur Levin
- Avidity Biosciences, Inc., 10578 Science Center Drive Suite 125. San Diego, California 92121, United States
| | - Venkata Ramana Doppalapudi
- Avidity Biosciences, Inc., 10578 Science Center Drive Suite 125. San Diego, California 92121, United States
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19
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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.
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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
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20
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King JJ, Chen K, Evans CW, Norret M, Almasri R, Pavlos NJ, Hui HY, Lin Q, Bhatt U, Young SG, Smith NM, Nikan M, Prestidge CA, Jiang H, Iyer KS. High-resolution visualisation of antisense oligonucleotide release from polymers in cells. Chem Sci 2024:d3sc06773d. [PMID: 39246363 PMCID: PMC11378015 DOI: 10.1039/d3sc06773d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Accepted: 08/20/2024] [Indexed: 09/10/2024] Open
Abstract
Antisense oligonucleotides (ASOs) are a well-established therapeutic modality based on RNA interference, but low cellular uptake, limited ability to direct ASO trafficking, and a range of intracellular barriers to successful activity compromise both gene silencing outcomes and clinical translations. Herein, we demonstrate that polymers can increase ASO internalisation via intracellular trafficking pathways that are distinct from lipid-based delivery reagents. For the first time, we spatially define internalisation and dissociation stages in the polymer-mediated cytosolic delivery of ASOs using Nanoscale Secondary Ion Mass Spectrometry (NanoSIMS), which enables visualisation of ASO localisation at the organelle level. We find that polymer-ASO complexes are imported into cells, from which free ASO enters the cytosol following complex dissociation. This information enables a better understanding of the intracellular trafficking pathways of nucleic acid therapeutics and may be exploited for therapeutic delivery to enhance the effectiveness of nucleic acid therapeutics in the future.
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Affiliation(s)
- Jessica J King
- School of Molecular Sciences, The University of Western Australia Perth WA 6009 Australia
- ARC Training Centre for Next-Generation Biomedical Analysis, The University of Western Australia Perth WA 6009 Australia
| | - Kai Chen
- School of Molecular Sciences, The University of Western Australia Perth WA 6009 Australia
- ARC Training Centre for Next-Generation Biomedical Analysis, The University of Western Australia Perth WA 6009 Australia
| | - Cameron W Evans
- School of Molecular Sciences, The University of Western Australia Perth WA 6009 Australia
- ARC Training Centre for Next-Generation Biomedical Analysis, The University of Western Australia Perth WA 6009 Australia
| | - Marck Norret
- School of Molecular Sciences, The University of Western Australia Perth WA 6009 Australia
- ARC Training Centre for Next-Generation Biomedical Analysis, The University of Western Australia Perth WA 6009 Australia
| | - Ruba Almasri
- School of Molecular Sciences, The University of Western Australia Perth WA 6009 Australia
- ARC Training Centre for Next-Generation Biomedical Analysis, The University of Western Australia Perth WA 6009 Australia
- UniSA Clinical & Health Sciences, University of South Australia Adelaide SA Australia
| | - Nathan J Pavlos
- School of Biomedical Sciences, The University of Western Australia Perth WA 6009 Australia
| | - Henry Yl Hui
- Translational Cancer Pathology Laboratory, School of Biomedical Sciences, The University of Western Australia Perth WA 6009 Australia
| | - Qiongxiang Lin
- School of Molecular Sciences, The University of Western Australia Perth WA 6009 Australia
- ARC Training Centre for Next-Generation Biomedical Analysis, The University of Western Australia Perth WA 6009 Australia
| | - Uditi Bhatt
- School of Molecular Sciences, The University of Western Australia Perth WA 6009 Australia
- ARC Training Centre for Next-Generation Biomedical Analysis, The University of Western Australia Perth WA 6009 Australia
| | - Stephen G Young
- Department of Medicine, University of California Los Angeles CA 90095 USA
| | - Nicole M Smith
- School of Molecular Sciences, The University of Western Australia Perth WA 6009 Australia
- ARC Training Centre for Next-Generation Biomedical Analysis, The University of Western Australia Perth WA 6009 Australia
| | - Mehran Nikan
- Ionis Pharmaceuticals, Inc. Carlsbad CA 92010 USA
| | - Clive A Prestidge
- UniSA Clinical & Health Sciences, University of South Australia Adelaide SA Australia
| | - Haibo Jiang
- School of Molecular Sciences, The University of Western Australia Perth WA 6009 Australia
- ARC Training Centre for Next-Generation Biomedical Analysis, The University of Western Australia Perth WA 6009 Australia
- Department of Chemistry, Faculty of Science, University of Hong Kong Pok Fu Lam Hong Kong
| | - K Swaminathan Iyer
- School of Molecular Sciences, The University of Western Australia Perth WA 6009 Australia
- ARC Training Centre for Next-Generation Biomedical Analysis, The University of Western Australia Perth WA 6009 Australia
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21
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Çakan E, Lara OD, Szymanowska A, Bayraktar E, Chavez-Reyes A, Lopez-Berestein G, Amero P, Rodriguez-Aguayo C. Therapeutic Antisense Oligonucleotides in Oncology: From Bench to Bedside. Cancers (Basel) 2024; 16:2940. [PMID: 39272802 PMCID: PMC11394571 DOI: 10.3390/cancers16172940] [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: 07/24/2024] [Revised: 08/16/2024] [Accepted: 08/17/2024] [Indexed: 09/15/2024] Open
Abstract
Advancements in our comprehension of tumor biology and chemoresistance have spurred the development of treatments that precisely target specific molecules within the body. Despite the expanding landscape of therapeutic options, there persists a demand for innovative approaches to address unmet clinical needs. RNA therapeutics have emerged as a promising frontier in this realm, offering novel avenues for intervention such as RNA interference and the utilization of antisense oligonucleotides (ASOs). ASOs represent a versatile class of therapeutics capable of selectively targeting messenger RNAs (mRNAs) and silencing disease-associated proteins, thereby disrupting pathogenic processes at the molecular level. Recent advancements in chemical modification and carrier molecule design have significantly enhanced the stability, biodistribution, and intracellular uptake of ASOs, thereby bolstering their therapeutic potential. While ASO therapy holds promise across various disease domains, including oncology, coronary angioplasty, neurological disorders, viral, and parasitic diseases, our review manuscript focuses specifically on the application of ASOs in targeted cancer therapies. Through a comprehensive examination of the latest research findings and clinical developments, we delve into the intricacies of ASO-based approaches to cancer treatment, shedding light on their mechanisms of action, therapeutic efficacy, and prospects.
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Affiliation(s)
- Elif Çakan
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
- Faculty of Medicine, Hacettepe University, Ankara 06100, Turkey
| | - Olivia D Lara
- Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
- Division of Gynecologic Oncology, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Anna Szymanowska
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Emine Bayraktar
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
- Department of Medical Biology, Faculty of Medicine, University of Gaziantep, Gaziantep 27310, Turkey
| | | | - Gabriel Lopez-Berestein
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Paola Amero
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Cristian Rodriguez-Aguayo
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
- Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
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22
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Caramiello AM, Pirota V. Novel Therapeutic Horizons: SNCA Targeting in Parkinson's Disease. Biomolecules 2024; 14:949. [PMID: 39199337 PMCID: PMC11352499 DOI: 10.3390/biom14080949] [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: 07/03/2024] [Revised: 07/29/2024] [Accepted: 08/02/2024] [Indexed: 09/01/2024] Open
Abstract
Alpha-synuclein (αSyn) aggregates are the primary component of Lewy bodies, which are pathological hallmarks of Parkinson's disease (PD). The toxicity of αSyn seems to increase with its elevated expression during injury, suggesting that therapeutic approaches focused on reducing αSyn burden in neurons could be beneficial. Additionally, studies have shown higher levels of SNCA mRNA in the midbrain tissues and substantia nigra dopaminergic neurons of sporadic PD post-mortem brains compared to controls. Therefore, the regulation of SNCA expression and inhibition of αSyn synthesis could play an important role in the pathogenesis of injury, resulting in an effective treatment approach for PD. In this context, we summarized the most recent and innovative strategies proposed that exploit the targeting of SNCA to regulate translation and efficiently knock down cytoplasmatic levels of αSyn. Significant progress has been made in developing antisense technologies for treating PD in recent years, with a focus on antisense oligonucleotides and short-interfering RNAs, which achieve high specificity towards the desired target. To provide a more exhaustive picture of this research field, we also reported less common but highly innovative strategies, including small molecules, designed to specifically bind 5'-untranslated regions and, targeting secondary nucleic acid structures present in the SNCA gene, whose formation can be modulated, acting as a transcription and translation control. To fully describe the efficiency of the reported strategies, the effect of αSyn reduction on cellular viability and dopamine homeostasis was also considered.
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Affiliation(s)
| | - Valentina Pirota
- Department of Chemistry, University of Pavia, Viale Taramelli 10, 27100 Pavia, Italy;
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23
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Abou Madawi NA, Darwish ZE, Omar EM. Targeted gene therapy for cancer: the impact of microRNA multipotentiality. Med Oncol 2024; 41:214. [PMID: 39088082 PMCID: PMC11294399 DOI: 10.1007/s12032-024-02450-1] [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: 06/10/2024] [Accepted: 07/12/2024] [Indexed: 08/02/2024]
Abstract
Cancer is a life-threatening disease and its management is difficult due to its complex nature. Cancer is characterized by genomic instability and tumor-associated inflammation of the supporting stoma. With the advances in omics science, a treatment strategy for cancer has emerged, which is based on targeting cancer-driving molecules, known as targeted therapy. Gene therapy, a form of targeted therapy, is the introduction of nucleic acids into living cells to replace a defective gene, promote or repress gene expression to treat a disease. MicroRNAs (miRNAs) are non-coding RNAs (ncRNAs) that regulate gene expression and thus are involved in physiological processes like cell proliferation, differentiation, and cell death. miRNAs control the actions of many genes. They are deregulated in cancer and their abnormal expression influences genetic and epigenetic alterations inducing carcinogenesis. In this review, we will explain the role of miRNAs in normal and abnormal gene expression and their usefulness in monitoring cancer patients. Besides, we will discuss miRNA-based therapy as a method of gene therapy and its impact on the success of cancer management.
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Affiliation(s)
- Nourhan A Abou Madawi
- Oral Pathology Department, Faculty of Dentistry, Alexandria University, Champollion Street, Azarita, 21521, Alexandria, Egypt.
| | - Zeinab E Darwish
- Oral Pathology Department, Faculty of Dentistry, Alexandria University, Champollion Street, Azarita, 21521, Alexandria, Egypt
| | - Enas M Omar
- Oral Pathology Department, Faculty of Dentistry, Alexandria University, Champollion Street, Azarita, 21521, Alexandria, Egypt
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24
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Shah M, Sharma A, Ayyad M, Swartz E, Jafrani D, Gala D. Targeting Apolipoprotein C-III for the Management of Severe Hypertriglyceridemia: Current Research and Future Directions. Cureus 2024; 16:e67091. [PMID: 39286687 PMCID: PMC11405074 DOI: 10.7759/cureus.67091] [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: 08/17/2024] [Indexed: 09/19/2024] Open
Abstract
Hypertriglyceridemia is characterized by elevated triglyceride levels in the blood, which increases the risk of cardiovascular disease and pancreatitis. This condition stems from multiple factors including lifestyle choices, genetics, and conditions such as diabetes and metabolic syndrome. Apolipoprotein C-III (APOC3), a protein for lipid metabolism, hinders enzymes necessary for breaking down triglycerides and thus plays a key role in hypertriglyceridemia. Variations in the APOC3 gene are associated with varying triglyceride levels among individuals. Recent genetic studies and clinical trials have shed light on the potential of targeting APOC3 as a potentially promising therapeutic modality of hypertriglyceridemia. Antisense oligonucleotides like volanesorsen have displayed effectiveness in lowering triglyceride levels in individuals with severe hypertriglyceridemia. This review article delves into how APOC3 influences triglyceride control and its potential use in targeting APOC3 to manage severe hypertriglyceridemia.
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Affiliation(s)
- Mili Shah
- Internal Medicine, American University of the Caribbean School of Medicine, Sint Maarten, SXM
| | - Abisheikh Sharma
- Internal Medicine, American University of the Caribbean School of Medicine, Sint Maarten, SXM
| | - Mohammed Ayyad
- Internal Medicine, Rutgers University New Jersey Medical School, Newark, USA
| | - Ethan Swartz
- Internal Medicine, Rutgers University New Jersey Medical School, Newark, USA
| | - Danyaal Jafrani
- Internal Medicine, Rutgers University New Jersey Medical School, Newark, USA
| | - Dhir Gala
- Internal Medicine, Rutgers University New Jersey Medical School, Newark, USA
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25
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Yuan W, Shi X, Lee LTO. RNA therapeutics in targeting G protein-coupled receptors: Recent advances and challenges. MOLECULAR THERAPY. NUCLEIC ACIDS 2024; 35:102195. [PMID: 38741614 PMCID: PMC11089380 DOI: 10.1016/j.omtn.2024.102195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 05/16/2024]
Abstract
G protein-coupled receptors (GPCRs) are the major targets of existing drugs for a plethora of human diseases and dominate the pharmaceutical market. However, over 50% of the GPCRs remain undruggable. To pursue a breakthrough and overcome this situation, there is significant clinical research for developing RNA-based drugs specifically targeting GPCRs, but none has been approved so far. RNA therapeutics represent a unique and promising approach to selectively targeting previously undruggable targets, including undruggable GPCRs. However, the development of RNA therapeutics faces significant challenges in areas of RNA stability and efficient in vivo delivery. This review presents an overview of the advances in RNA therapeutics and the diverse types of nanoparticle RNA delivery systems. It also describes the potential applications of GPCR-targeted RNA drugs for various human diseases.
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Affiliation(s)
- Wanjun Yuan
- Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa 999078, Macau, China
| | - Xiangyang Shi
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai 201620, People’s Republic of China
| | - Leo Tsz On Lee
- Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa 999078, Macau, China
- Ministry of Education Frontiers Science Center for Precision Oncology, University of Macau, Taipa 999078, Macau, China
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26
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Elnaggar MG, He Y, Yeo Y. Recent trends in the delivery of RNA drugs: Beyond the liver, more than vaccine. Eur J Pharm Biopharm 2024; 197:114203. [PMID: 38302049 PMCID: PMC10947810 DOI: 10.1016/j.ejpb.2024.114203] [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: 11/30/2023] [Revised: 01/12/2024] [Accepted: 01/29/2024] [Indexed: 02/03/2024]
Abstract
RNAs are known for versatile functions and therapeutic utility. They have gained significant interest since the approval of several RNA drugs, including COVID-19 mRNA vaccines and therapeutic agents targeting liver diseases. There are increasing expectations for a new class of RNA drugs for broader applications. Successful development of RNA drugs for new applications hinges on understanding their diverse functions and structures. In this review, we explore the last five years of literature to understand current approaches to formulate a spectrum of RNA drugs, focusing on new efforts to expand their applications beyond vaccines and liver diseases.
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Affiliation(s)
- Marwa G Elnaggar
- Department of Industrial and Molecular Pharmaceutics, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, USA; Department of Industrial Pharmacy, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt
| | - Yanying He
- Department of Industrial and Molecular Pharmaceutics, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, USA
| | - Yoon Yeo
- Department of Industrial and Molecular Pharmaceutics, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, USA; Purdue University Institute for Cancer Research, 201 South University Street, West Lafayette, IN 47907, USA; Weldon School of Biomedical Engineering, Purdue University, 206 S Martin Jischke Drive, West Lafayette, IN 47907, USA.
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27
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MacLelland V, Kravitz M, Gupta A. Therapeutic and diagnostic applications of antisense peptide nucleic acids. MOLECULAR THERAPY. NUCLEIC ACIDS 2024; 35:102086. [PMID: 38204913 PMCID: PMC10777018 DOI: 10.1016/j.omtn.2023.102086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/12/2024]
Abstract
Peptide nucleic acids (PNAs) are synthetic nucleic acid analogs with a neutral N-(2-aminoethyl) glycine backbone. PNAs possess unique physicochemical characteristics such as increased resistance to enzymatic degradation, ionic strength and stability over a wide range of temperatures and pH, and low intrinsic electrostatic repulsion against complementary target oligonucleotides. PNA has been widely used as an antisense oligonucleotide (ASO). Despite the favorable characteristics of PNA, in comparison with other ASO technologies, the use of antisense PNA for novel therapeutics has lagged. This review provides a brief overview of PNA, its antisense mechanisms of action, delivery strategies, and highlights successful applications of PNA, focusing on anti-pathogenic, anti-neurodegenerative disease, anti-cancer, and diagnostic agents. For each application, several studies are discussed focusing on the different target sites of the PNA, design of different PNAs and the therapeutic outcome in different cell lines and animal models. Thereafter, persisting limitations slowing the successful integration of antisense PNA therapeutics are discussed in order to highlight actionable next steps in the development and optimization of PNA as an ASO.
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Affiliation(s)
- Victoria MacLelland
- Department of Pharmaceutical Sciences, University of Saint Joseph, West Hartford, CT 06117, USA
| | - Madeline Kravitz
- Department of Pharmaceutical Sciences, University of Saint Joseph, West Hartford, CT 06117, USA
| | - Anisha Gupta
- Department of Pharmaceutical Sciences, University of Saint Joseph, West Hartford, CT 06117, USA
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28
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Zareie AR, Dabral P, Verma SC. G-Quadruplexes in the Regulation of Viral Gene Expressions and Their Impacts on Controlling Infection. Pathogens 2024; 13:60. [PMID: 38251367 PMCID: PMC10819198 DOI: 10.3390/pathogens13010060] [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: 11/15/2023] [Revised: 01/05/2024] [Accepted: 01/05/2024] [Indexed: 01/23/2024] Open
Abstract
G-quadruplexes (G4s) are noncanonical nucleic acid structures that play significant roles in regulating various biological processes, including replication, transcription, translation, and recombination. Recent studies have identified G4s in the genomes of several viruses, such as herpes viruses, hepatitis viruses, and human coronaviruses. These structures are implicated in regulating viral transcription, replication, and virion production, influencing viral infectivity and pathogenesis. G4-stabilizing ligands, like TMPyP4, PhenDC3, and BRACO19, show potential antiviral properties by targeting and stabilizing G4 structures, inhibiting essential viral life-cycle processes. This review delves into the existing literature on G4's involvement in viral regulation, emphasizing specific G4-stabilizing ligands. While progress has been made in understanding how these ligands regulate viruses, further research is needed to elucidate the mechanisms through which G4s impact viral processes. More research is necessary to develop G4-stabilizing ligands as novel antiviral agents. The increasing body of literature underscores the importance of G4s in viral biology and the development of innovative therapeutic strategies against viral infections. Despite some ligands' known regulatory effects on viruses, a deeper comprehension of the multifaceted impact of G4s on viral processes is essential. This review advocates for intensified research to unravel the intricate relationship between G4s and viral processes, paving the way for novel antiviral treatments.
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Affiliation(s)
| | | | - Subhash C. Verma
- Department of Microbiology and Immunology, University of Nevada, Reno School of Medicine, 1664 N Virginia Street, Reno, NV 89557, USA; (A.R.Z.); (P.D.)
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29
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Vuong HL, Lan CT, Le HTT. The development and technologies of RNA therapeutics. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2024; 203:13-39. [PMID: 38359995 DOI: 10.1016/bs.pmbts.2023.12.017] [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
Since it was discovered for over 20 years ago, the potentiality of siRNAs in gene silencing in vitro and in vivo models has been recognized. Several studies in the new generation, molecular mechanisms, target attachment, and purification of RNA have supported the development of RNA therapeutics for a variety of applications. RNA therapeutics are growing rapidly with various platforms contributing to the standard of personalized medicine and rare disease treatment. Therefore, understanding the development and technologies of RNA therapeutics becomes a crucial point for new drug generation. Here, the primary purpose of this review is to provide a general view of six therapeutic categories that make up RNA-based therapeutic approaches, including RNA-target therapeutics, protein-targeted therapeutics, cellular reprogramming and tissues engineering, RNA-based protein replacement therapeutics, RNA-based genome editing, and RNA-based immunotherapies based on non-coding RNAs and coding RNA. Furthermore, we present an overview of the RNA strategies regarding viral approaches and nonviral approaches in designing a new generation of RNA technologies. The advantages and challenges of using RNA therapeutics are also discussed along with various approaches for RNA delivery. Therefore, this review is designed to provide updated reference evidence of RNA therapeutics in the battle against rare or difficult-to-treat diseases for researchers in this field.
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Affiliation(s)
- Huong Lan Vuong
- Pharmacy Department, National Hospital for Tropical Diseases, Hanoi, Vietnam
| | - Chu Thanh Lan
- Department of Regenerative Medicine, Institute of Tissue Regeneration, College of Medicine, Soonchunghyang University, South Korea
| | - Hien Thi Thu Le
- Intestinal Signaling and Epigenetics, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
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30
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Diwan R, Bhatt HN, Beaven E, Nurunnabi M. Emerging delivery approaches for targeted pulmonary fibrosis treatment. Adv Drug Deliv Rev 2024; 204:115147. [PMID: 38065244 PMCID: PMC10787600 DOI: 10.1016/j.addr.2023.115147] [Citation(s) in RCA: 18] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Revised: 11/02/2023] [Accepted: 11/29/2023] [Indexed: 01/01/2024]
Abstract
Pulmonary fibrosis (PF) is a progressive, and life-threatening interstitial lung disease which causes scarring in the lung parenchyma and thereby affects architecture and functioning of lung. It is an irreversible damage to lung functioning which is related to epithelial cell injury, immense accumulation of immune cells and inflammatory cytokines, and irregular recruitment of extracellular matrix. The inflammatory cytokines trigger the differentiation of fibroblasts into activated fibroblasts, also known as myofibroblasts, which further increase the production and deposition of collagen at the injury sites in the lung. Despite the significant morbidity and mortality associated with PF, there is no available treatment that efficiently and effectively treats the disease by reversing their underlying pathologies. In recent years, many therapeutic regimens, for instance, rho kinase inhibitors, Smad signaling pathway inhibitors, p38, BCL-xL/ BCL-2 and JNK pathway inhibitors, have been found to be potent and effective in treating PF, in preclinical stages. However, due to non-selectivity and non-specificity, the therapeutic molecules also result in toxicity mediated severe side effects. Hence, this review demonstrates recent advances on PF pathology, mechanism and targets related to PF, development of various drug delivery systems based on small molecules, RNAs, oligonucleotides, peptides, antibodies, exosomes, and stem cells for the treatment of PF and the progress of various therapeutic treatments in clinical trials to advance PF treatment.
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Affiliation(s)
- Rimpy Diwan
- Department of Pharmaceutical Sciences, School of Pharmacy, The University of Texas El Paso, El Paso, TX 79902, United States; Department of Biomedical Engineering, College of Engineering, The University of Texas El Paso, El Paso, TX 79968, United States
| | - Himanshu N Bhatt
- Department of Pharmaceutical Sciences, School of Pharmacy, The University of Texas El Paso, El Paso, TX 79902, United States; Department of Biomedical Engineering, College of Engineering, The University of Texas El Paso, El Paso, TX 79968, United States
| | - Elfa Beaven
- Department of Pharmaceutical Sciences, School of Pharmacy, The University of Texas El Paso, El Paso, TX 79902, United States; Department of Biomedical Engineering, College of Engineering, The University of Texas El Paso, El Paso, TX 79968, United States
| | - Md Nurunnabi
- Department of Pharmaceutical Sciences, School of Pharmacy, The University of Texas El Paso, El Paso, TX 79902, United States; Department of Biomedical Engineering, College of Engineering, The University of Texas El Paso, El Paso, TX 79968, United States; The Border Biomedical Research Center, The University of Texas El Paso, El Paso, TX 79968, United States.
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31
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Qiao B, Liu X, Wang B, Wei S. The role of periostin in cardiac fibrosis. Heart Fail Rev 2024; 29:191-206. [PMID: 37870704 DOI: 10.1007/s10741-023-10361-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/10/2023] [Indexed: 10/24/2023]
Abstract
Cardiac fibrosis, which is the buildup of proteins in the connective tissues of the heart, can lead to end-stage extracellular matrix (ECM) remodeling and ultimately heart failure. Cardiac remodeling involves changes in gene expression in cardiac cells and ECM, which significantly leads to the morbidity and mortality in heart failure. However, despite extensive research, the elusive intricacies underlying cardiac fibrosis remain unidentified. Periostin, an extracellular matrix (ECM) protein of the fasciclin superfamily, acts as a scaffold for building complex architectures in the ECM, which improves intermolecular interactions and augments the mechanical properties of connective tissues. Recent research has shown that periostin not only contributes to normal ECM homeostasis in a healthy heart but also serves as a potent inducible regulator of cellular reorganization in cardiac fibrosis. Here, we reviewed the constitutive domain of periostin and its interaction with other ECM proteins. We have also discussed the critical pathophysiological functions of periostin in cardiac remodeling mechanisms, including two distinct yet potentially intertwined mechanisms. Furthermore, we will focus on the intrinsic complexities within periostin research, particularly surrounding the contentious issues observed in experimental findings.
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Affiliation(s)
- Bao Qiao
- Department of Emergency and Chest Pain Center, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China
| | - Xuehao Liu
- Department of Emergency and Chest Pain Center, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China
| | - Bailu Wang
- Clinical Trial Center, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China
| | - Shujian Wei
- Department of Emergency and Chest Pain Center, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China.
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China.
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China.
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32
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Kola NS, Patel D, Thakur A. RNA-Based Vaccines and Therapeutics Against Intracellular Pathogens. Methods Mol Biol 2024; 2813:321-370. [PMID: 38888787 DOI: 10.1007/978-1-0716-3890-3_21] [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] [Indexed: 06/20/2024]
Abstract
RNA-based vaccines have sparked a paradigm shift in the treatment and prevention of diseases by nucleic acid medicines. There has been a notable surge in the development of nucleic acid therapeutics and vaccines following the global approval of the two messenger RNA-based COVID-19 vaccines. This growth is fueled by the exploration of numerous RNA products in preclinical stages, offering several advantages over conventional methods, i.e., safety, efficacy, scalability, and cost-effectiveness. In this chapter, we provide an overview of various types of RNA and their mechanisms of action for stimulating immune responses and inducing therapeutic effects. Furthermore, this chapter delves into the varying delivery systems, particularly emphasizing the use of nanoparticles to deliver RNA. The choice of delivery system is an intricate process involved in developing nucleic acid medicines that significantly enhances their stability, biocompatibility, and site-specificity. Additionally, this chapter sheds light on the current landscape of clinical trials of RNA therapeutics and vaccines against intracellular pathogens.
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Affiliation(s)
- Naga Suresh Kola
- Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, SK, Canada
| | - Dhruv Patel
- Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, SK, Canada
| | - Aneesh Thakur
- Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, SK, Canada.
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33
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Cao R, Chen C, Wen J, Zhao W, Zhang C, Sun L, Yuan L, Wu C, Shan L, Xi M, Sun H. Recent advances in targeting leucine-rich repeat kinase 2 as a potential strategy for the treatment of Parkinson's disease. Bioorg Chem 2023; 141:106906. [PMID: 37837728 DOI: 10.1016/j.bioorg.2023.106906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 09/24/2023] [Accepted: 10/06/2023] [Indexed: 10/16/2023]
Abstract
Parkinson's disease (PD) is the second most common neurodegenerative disease. Several single gene mutations involved in PD have been identified such as leucine-rich repeat kinase 2 (LRRK2), the most common cause of sporadic and familial PD. Its mutations have attracted much attention to therapeutically targeting this kinase. To date, many compounds including small chemical molecules with diverse scaffolds and RNA agents have been developed with significant amelioration in preclinical PD models. Currently, five candidates, DNL201, DNL151, WXWH0226, NEU-723 and BIIB094, have advanced to clinical trials for PD treatment. In this review, we describe the structure, pathogenic mutations and the mechanism of LRRK2, and summarize the development of LRRK2 inhibitors in preclinical and clinical studies, trying to provide an insight into targeting LRRK2 for PD intervention in future.
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Affiliation(s)
- Ruiwei Cao
- Zhejiang Engineering Research Center of Fat-soluble Vitamin, Shaoxing University, Shaoxing 312000, China; Zhejiang Medicine Co. Ltd., Shaoxing 312500, China
| | - Caiping Chen
- Zhejiang Engineering Research Center of Fat-soluble Vitamin, Shaoxing University, Shaoxing 312000, China; Zhejiang Medicine Co. Ltd., Shaoxing 312500, China
| | - Jing Wen
- Zhejiang Medicine Co. Ltd., Shaoxing 312500, China
| | - Weihe Zhao
- Zhejiang Medicine Co. Ltd., Shaoxing 312500, China
| | | | - Longhui Sun
- Zhejiang Medicine Co. Ltd., Shaoxing 312500, China
| | - Liyan Yuan
- Zhejiang Medicine Co. Ltd., Shaoxing 312500, China
| | - Chunlei Wu
- Zhejiang Engineering Research Center of Fat-soluble Vitamin, Shaoxing University, Shaoxing 312000, China; College of Chemistry and Chemical Engineering, Shaoxing University, Shaoxing 312000, China
| | - Lei Shan
- Zhejiang Engineering Research Center of Fat-soluble Vitamin, Shaoxing University, Shaoxing 312000, China
| | - Meiyang Xi
- Zhejiang Engineering Research Center of Fat-soluble Vitamin, Shaoxing University, Shaoxing 312000, China; College of Chemistry and Chemical Engineering, Shaoxing University, Shaoxing 312000, China.
| | - Haopeng Sun
- Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
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Hasan MN, Mosharaf MP, Uddin KS, Das KR, Sultana N, Noorunnahar M, Naim D, Mollah MNH. Genome-Wide Identification and Characterization of Major RNAi Genes Highlighting Their Associated Factors in Cowpea ( Vigna unguiculata (L.) Walp.). BIOMED RESEARCH INTERNATIONAL 2023; 2023:8832406. [PMID: 38046903 PMCID: PMC10691899 DOI: 10.1155/2023/8832406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 09/07/2023] [Accepted: 10/30/2023] [Indexed: 12/05/2023]
Abstract
In different regions of the world, cowpea (Vigna unguiculata (L.) Walp.) is an important vegetable and an excellent source of protein. It lessens the malnutrition of the underprivileged in developing nations and has some positive effects on health, such as a reduction in the prevalence of cancer and cardiovascular disease. However, occasionally, certain biotic and abiotic stresses caused a sharp fall in cowpea yield. Major RNA interference (RNAi) genes like Dicer-like (DCL), Argonaute (AGO), and RNA-dependent RNA polymerase (RDR) are essential for the synthesis of their associated factors like domain, small RNAs (sRNAs), transcription factors, micro-RNAs, and cis-acting factors that shield plants from biotic and abiotic stresses. In this study, applying BLASTP search and phylogenetic tree analysis with reference to the Arabidopsis RNAi (AtRNAi) genes, we discovered 28 VuRNAi genes, including 7 VuDCL, 14 VuAGO, and 7 VuRDR genes in cowpea. We looked at the domains, motifs, gene structures, chromosomal locations, subcellular locations, gene ontology (GO) terms, and regulatory factors (transcription factors, micro-RNAs, and cis-acting elements (CAEs)) to characterize the VuRNAi genes and proteins in cowpea in response to stresses. Predicted VuDCL1, VuDCL2(a, b), VuAGO7, VuAGO10, and VuRDR6 genes might have an impact on cowpea growth, development of the vegetative and flowering stages, and antiviral defense. The VuRNAi gene regulatory features miR395 and miR396 might contribute to grain quality improvement, immunity boosting, and pathogen infection resistance under salinity and drought conditions. Predicted CAEs from the VuRNAi genes might play a role in plant growth and development, improving grain quality and production and protecting plants from biotic and abiotic stresses. Therefore, our study provides crucial information about the functional roles of VuRNAi genes and their associated components, which would aid in the development of future cowpeas that are more resilient to biotic and abiotic stress. The manuscript is available as a preprint at this link: doi:10.1101/2023.02.15.528631v1.
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Affiliation(s)
- Mohammad Nazmol Hasan
- Department of Statistics, Bangabandhu Sheikh Mujibur Rahman Agricultural University, Gazipur 1706, Bangladesh
| | - Md Parvez Mosharaf
- School of Business, Faculty of Business, Education, Law and Arts, University of Southern Queensland, Toowoomba, QLD 4350, Australia
| | - Khandoker Saif Uddin
- Department of Quantitative Science (Statistics), International University of Business Agriculture and Technology (IUBAT), Uttara, Bangladesh
| | - Keya Rani Das
- Department of Statistics, Bangabandhu Sheikh Mujibur Rahman Agricultural University, Gazipur 1706, Bangladesh
| | - Nasrin Sultana
- Department of Statistics, Bangabandhu Sheikh Mujibur Rahman Agricultural University, Gazipur 1706, Bangladesh
| | - Mst. Noorunnahar
- Department of Statistics, Bangabandhu Sheikh Mujibur Rahman Agricultural University, Gazipur 1706, Bangladesh
| | - Darun Naim
- Department of Botany, Faculty of Biological Sciences, University of Rajshahi, Rajshahi 6205, Bangladesh
- Bioinformatics Lab, Department of Statistics, Faculty of Science, University of Rajshahi, Rajshahi 6205, Bangladesh
| | - Md. Nurul Haque Mollah
- Bioinformatics Lab, Department of Statistics, Faculty of Science, University of Rajshahi, Rajshahi 6205, Bangladesh
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Rivas VN, Stern JA, Ueda Y. The Role of Personalized Medicine in Companion Animal Cardiology. Vet Clin North Am Small Anim Pract 2023; 53:1255-1276. [PMID: 37423841 PMCID: PMC11184409 DOI: 10.1016/j.cvsm.2023.05.016] [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] [Indexed: 07/11/2023]
Abstract
Cardiomyopathies remain one of the most common inherited cardiac diseases in both human and veterinary patients. To date, well over 100 mutated genes are known to cause cardiomyopathies in humans with only a handful known in cats and dogs. This review highlights the need and use of personalized one-health approaches to cardiovascular case management and advancement in pharmacogenetic-based therapy in veterinary medicine. Personalized medicine holds promise in understanding the molecular basis of disease and ultimately will unlock the next generation of targeted novel pharmaceuticals and aid in the reversal of detrimental effects at a molecular level.
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Affiliation(s)
- Victor N Rivas
- Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California-Davis, One Shields Avenue, Davis, CA 95616, USA; Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, 1038 William Moore Drive, Raleigh, NC 27606, USA
| | - Joshua A Stern
- Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California-Davis, One Shields Avenue, Davis, CA 95616, USA; Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, 1038 William Moore Drive, Raleigh, NC 27606, USA
| | - Yu Ueda
- Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, 1038 William Moore Drive, Raleigh, NC 27606, USA.
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Abstract
PURPOSE OF REVIEW The goal of this review is to present the pharmacodynamic effectiveness as well as the clinical efficacy and safety of investigational antisense oligonucleotides (ASOs) and small interference RNAs (siRNAs) drugs that specifically target lipoprotein(a) (Lp(a)). The review will discuss whether the existing lipid-lowering therapies are adequate to treat high Lp(a) levels or whether it is necessary to use the emerging new therapeutic approaches which are based on the current RNA technologies. RECENT FINDINGS Lipoprotein(a) (Lp(a)) is a causal risk factor for atherosclerotic cardiovascular disease (ASCVD), independent of other conventional risk factors. High Lp(a) levels are also independently associated with an increased risk of aortic stenosis progression rate. Plasma Lp(a) levels are primarily genetically determined by variation in the LPA gene coding for apo(a). All secondary prevention trials have demonstrated that the existing hypolipidemic therapies are not adequate to reduce Lp(a) levels to such an extent that could lead to a substantial reduction of ASCVD risk. This has led to the development of new drugs that target the mRNA transcript of LPA and efficiently inhibit Lp(a) synthesis leading to potent Lp(a) reduction. These new drugs are the ASO pelacarsen and the siRNAs olpasiran and SLN360. Recent pharmacodynamic studies showed that all these drugs potently reduce Lp(a) up to 98%, in a dose-dependent manner. Ongoing clinical trials will determine the Lp(a)-lowering efficacy, tolerability, and safety of these drugs as well as their potential effectiveness in reducing the ASCVD risk attributed to high plasma Lp(a) levels. We are not ready today to significantly reduce plasma Lp(a). Emerging therapies potently decrease Lp(a) and ongoing clinical trials will determine their effectiveness in reducing ASCVD risk in subjects with high Lp(a) levels.
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Affiliation(s)
- Alexandros D Tselepis
- Atherothrombosis Research Centre/Laboratory of Biochemistry, Department of Chemistry, University of Ioannina, 45110, Ioannina, Greece.
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Das NC, Chakraborty P, Nandy S, Dey A, Malik T, Mukherjee S. Programmed cell death pathways as targets for developing antifilarial drugs: Lessons from the recent findings. J Cell Mol Med 2023; 27:2819-2840. [PMID: 37605891 PMCID: PMC10538269 DOI: 10.1111/jcmm.17913] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 07/17/2023] [Accepted: 08/09/2023] [Indexed: 08/23/2023] Open
Abstract
More than half a century has passed since the introduction of the National Filariasis Control Program; however, as of 2023, lymphatic filariasis (LF) still prevails globally, particularly in the tropical and subtropical regions, posing a substantial challenge to the objective of worldwide elimination. LF is affecting human beings and its economically important livestock leading to a crucial contributor to morbidities and disabilities. The current scenario has been blowing up alarms of attention to develop potent therapeutics and strategies having efficiency against the adult stage of filarial nematodes. In this context, the exploration of a suitable drug target that ensures lethality to macro and microfilariae is now our first goal to achieve. Apoptosis has been the potential target across all three stages of filarial nematodes viz. oocytes, microfilariae (mf) and adults resulting in filarial death after receiving the signal from the reactive oxygen species (ROS) and executed through intrinsic and extrinsic pathways. Hence, it is considered a leading target for developing antifilarial drugs. Herein, we have shown the efficacy of several natural and synthetic compounds/nanoformulations in triggering the apoptotic death of filarial parasites with little or no toxicity to the host body system.
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Affiliation(s)
- Nabarun Chandra Das
- Integrative Biochemistry & Immunology Laboratory, Department of Animal ScienceKazi Nazrul UniversityAsansolIndia
| | - Pritha Chakraborty
- Integrative Biochemistry & Immunology Laboratory, Department of Animal ScienceKazi Nazrul UniversityAsansolIndia
| | - Samapika Nandy
- Department of Life SciencePresidency UniversityKolkataIndia
- School of PharmacyGraphic Era Hill UniversityDehradunIndia
| | - Abhijit Dey
- Department of Life SciencePresidency UniversityKolkataIndia
| | | | - Suprabhat Mukherjee
- Integrative Biochemistry & Immunology Laboratory, Department of Animal ScienceKazi Nazrul UniversityAsansolIndia
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Babalola BA, Akinsuyi OS, Folajimi EO, Olujimi F, Otunba AA, Chikere B, Adewumagun IA, Adetobi TE. Exploring the future of SARS-CoV-2 treatment after the first two years of the pandemic: A comparative study of alternative therapeutics. Biomed Pharmacother 2023; 165:115099. [PMID: 37406505 DOI: 10.1016/j.biopha.2023.115099] [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: 05/12/2023] [Revised: 06/27/2023] [Accepted: 06/27/2023] [Indexed: 07/07/2023] Open
Abstract
One of the most pressing challenges associated with SARS-CoV-2 treatment is the emergence of new variants that may be more transmissible, cause more severe disease, or be resistant to current treatments and vaccines. The emergence of SARS-CoV-2 has led to a global pandemic, resulting in millions of deaths worldwide. Various strategies have been employed to combat the virus, including neutralizing monoclonal antibodies (mAbs), CRISPR/Cas13, and antisense oligonucleotides (ASOs). While vaccines and small molecules have proven to be an effective means of preventing severe COVID-19 and reducing transmission rates, the emergence of new virus variants poses a challenge to their effectiveness. Monoclonal antibodies have shown promise in treating early-stage COVID-19, but their effectiveness is limited in severe cases and the emergence of new variants may reduce their binding affinity. CRISPR/Cas13 has shown potential in targeting essential viral genes, but its efficiency, specificity, and delivery to the site of infection are major limitations. ASOs have also been shown to be effective in targeting viral RNA, but they face similar challenges to CRISPR/Cas13 in terms of delivery and potential off-target effects. In conclusion, a combination of these strategies may provide a more effective means of combating SARS-CoV-2, and future research should focus on improving their efficiency, specificity, and delivery to the site of infection. It is evident that the continued research and development of these alternative therapies will be essential in the ongoing fight against SARS-CoV-2 and its potential future variants.
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Affiliation(s)
| | | | | | - Folakemi Olujimi
- Department of Biochemistry, Mountain Top University, Prayer-City, Ogun State, Nigeria
| | | | - Bruno Chikere
- Department of Biochemistry, Covenant University, Ogun State, Nigeria
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Buthelezi LA, Pillay S, Ntuli NN, Gcanga L, Guler R. Antisense Therapy for Infectious Diseases. Cells 2023; 12:2119. [PMID: 37626929 PMCID: PMC10453568 DOI: 10.3390/cells12162119] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 08/15/2023] [Accepted: 08/17/2023] [Indexed: 08/27/2023] Open
Abstract
Infectious diseases, particularly Tuberculosis (TB) caused by Mycobacterium tuberculosis, pose a significant global health challenge, with 1.6 million reported deaths in 2021, making it the most fatal disease caused by a single infectious agent. The rise of drug-resistant infectious diseases adds to the urgency of finding effective and safe intervention therapies. Antisense therapy uses antisense oligonucleotides (ASOs) that are short, chemically modified, single-stranded deoxyribonucleotide molecules complementary to their mRNA target. Due to their designed target specificity and inhibition of a disease-causing gene at the mRNA level, antisense therapy has gained interest as a potential therapeutic approach. This type of therapy is currently utilized in numerous diseases, such as cancer and genetic disorders. Currently, there are limited but steadily increasing studies available that report on the use of ASOs as treatment for infectious diseases. This review explores the sustainability of FDA-approved and preclinically tested ASOs as a treatment for infectious diseases and the adaptability of ASOs for chemical modifications resulting in reduced side effects with improved drug delivery; thus, highlighting the potential therapeutic uses of ASOs for treating infectious diseases.
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Affiliation(s)
- Lwanda Abonga Buthelezi
- International Centre for Genetic Engineering and Biotechnology, Cape Town Component, Cape Town 7925, South Africa; (L.A.B.); (S.P.); (N.N.N.); (L.G.)
- Department of Pathology, Division of Immunology, Institute of Infectious Diseases and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa
| | - Shandre Pillay
- International Centre for Genetic Engineering and Biotechnology, Cape Town Component, Cape Town 7925, South Africa; (L.A.B.); (S.P.); (N.N.N.); (L.G.)
- Department of Pathology, Division of Immunology, Institute of Infectious Diseases and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa
| | - Noxolo Nokukhanya Ntuli
- International Centre for Genetic Engineering and Biotechnology, Cape Town Component, Cape Town 7925, South Africa; (L.A.B.); (S.P.); (N.N.N.); (L.G.)
- Department of Pathology, Division of Immunology, Institute of Infectious Diseases and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa
| | - Lorna Gcanga
- International Centre for Genetic Engineering and Biotechnology, Cape Town Component, Cape Town 7925, South Africa; (L.A.B.); (S.P.); (N.N.N.); (L.G.)
- Department of Pathology, Division of Immunology, Institute of Infectious Diseases and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa
| | - Reto Guler
- International Centre for Genetic Engineering and Biotechnology, Cape Town Component, Cape Town 7925, South Africa; (L.A.B.); (S.P.); (N.N.N.); (L.G.)
- Department of Pathology, Division of Immunology, Institute of Infectious Diseases and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa
- Faculty of Health Sciences, Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town 7925, South Africa
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Udu-Ituma S, Adélaïde J, Le TK, Omabe K, Finetti P, Paris C, Guille A, Bertucci F, Birnbaum D, Rocchi P, Chaffanet M. ZNF703 mRNA-Targeting Antisense Oligonucleotide Blocks Cell Proliferation and Induces Apoptosis in Breast Cancer Cell Lines. Pharmaceutics 2023; 15:1930. [PMID: 37514116 PMCID: PMC10384502 DOI: 10.3390/pharmaceutics15071930] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 06/29/2023] [Accepted: 06/30/2023] [Indexed: 07/30/2023] Open
Abstract
The luminal B molecular subtype of breast cancers (BC) accounts for more than a third of BCs and is associated with aggressive clinical behavior and poor prognosis. The use of endocrine therapy in BC treatment has significantly contributed to the decrease in the number of deaths in recent years. However, most BC patients with prolonged exposure to estrogen receptor (ER) selective modulators such as tamoxifen develop resistance and become non-responsive over time. Recent studies have implicated overexpression of the ZNF703 gene in BC resistance to endocrine drugs, thereby highlighting ZNF703 inhibition as an attractive modality in BC treatment, especially luminal B BCs. However, there is no known inhibitor of ZNF703 due to its nuclear association and non-enzymatic activity. Here, we have developed an antisense oligonucleotide (ASO) against ZNF703 mRNA and shown that it downregulates ZNF703 protein expression. ZNF703 inhibition decreased cell proliferation and induced apoptosis. Combined with cisplatin, the anti-cancer effects of ZNF703-ASO9 were improved. Moreover, our work shows that ASO technology may be used to increase the number of targetable cancer genes.
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Affiliation(s)
- Sandra Udu-Ituma
- Equipe Labellisée Ligue Nationale Contre le Cancer, Predictive Oncology Laboratory, Marseille Research Cancer Center, INSERM U1068, CNRS U7258, Institut Paoli-Calmettes, Aix Marseille University, 13009 Marseille, France
- Department of Biology, Alex Ekwueme Federal University Ndufu-Alike Ikwo, Abakaliki P.M.B. 1010, Ebonyi State, Nigeria
- European Center for Research in Medical Imaging, Aix-Marseille University, 13005 Marseille, France
| | - José Adélaïde
- Equipe Labellisée Ligue Nationale Contre le Cancer, Predictive Oncology Laboratory, Marseille Research Cancer Center, INSERM U1068, CNRS U7258, Institut Paoli-Calmettes, Aix Marseille University, 13009 Marseille, France
| | - Thi Khanh Le
- Equipe Labellisée Ligue Nationale Contre le Cancer, Predictive Oncology Laboratory, Marseille Research Cancer Center, INSERM U1068, CNRS U7258, Institut Paoli-Calmettes, Aix Marseille University, 13009 Marseille, France
- European Center for Research in Medical Imaging, Aix-Marseille University, 13005 Marseille, France
| | - Kenneth Omabe
- Equipe Labellisée Ligue Nationale Contre le Cancer, Predictive Oncology Laboratory, Marseille Research Cancer Center, INSERM U1068, CNRS U7258, Institut Paoli-Calmettes, Aix Marseille University, 13009 Marseille, France
| | - Pascal Finetti
- Equipe Labellisée Ligue Nationale Contre le Cancer, Predictive Oncology Laboratory, Marseille Research Cancer Center, INSERM U1068, CNRS U7258, Institut Paoli-Calmettes, Aix Marseille University, 13009 Marseille, France
| | - Clément Paris
- Equipe Labellisée Ligue Nationale Contre le Cancer, Predictive Oncology Laboratory, Marseille Research Cancer Center, INSERM U1068, CNRS U7258, Institut Paoli-Calmettes, Aix Marseille University, 13009 Marseille, France
| | - Arnaud Guille
- Equipe Labellisée Ligue Nationale Contre le Cancer, Predictive Oncology Laboratory, Marseille Research Cancer Center, INSERM U1068, CNRS U7258, Institut Paoli-Calmettes, Aix Marseille University, 13009 Marseille, France
| | - François Bertucci
- Equipe Labellisée Ligue Nationale Contre le Cancer, Predictive Oncology Laboratory, Marseille Research Cancer Center, INSERM U1068, CNRS U7258, Institut Paoli-Calmettes, Aix Marseille University, 13009 Marseille, France
| | - Daniel Birnbaum
- Equipe Labellisée Ligue Nationale Contre le Cancer, Predictive Oncology Laboratory, Marseille Research Cancer Center, INSERM U1068, CNRS U7258, Institut Paoli-Calmettes, Aix Marseille University, 13009 Marseille, France
| | - Palma Rocchi
- Equipe Labellisée Ligue Nationale Contre le Cancer, Predictive Oncology Laboratory, Marseille Research Cancer Center, INSERM U1068, CNRS U7258, Institut Paoli-Calmettes, Aix Marseille University, 13009 Marseille, France
- European Center for Research in Medical Imaging, Aix-Marseille University, 13005 Marseille, France
| | - Max Chaffanet
- Equipe Labellisée Ligue Nationale Contre le Cancer, Predictive Oncology Laboratory, Marseille Research Cancer Center, INSERM U1068, CNRS U7258, Institut Paoli-Calmettes, Aix Marseille University, 13009 Marseille, France
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Tekintaş Y, Temel A. Antisense oligonucleotides: a promising therapeutic option against infectious diseases. NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS 2023; 43:1-39. [PMID: 37395450 DOI: 10.1080/15257770.2023.2228841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Accepted: 06/19/2023] [Indexed: 07/04/2023]
Abstract
Infectious diseases have been one of the biggest health problems of humanity for centuries. Nucleic acid-based therapeutics have received attention in recent years with their effectiveness in the treatment of various infectious diseases and vaccine development studies. This review aims to provide a comprehensive understanding of the basic properties underlying the mechanism of antisense oligonucleotides (ASOs), their applications, and their challenges. The efficient delivery of ASOs is the greatest challenge for their therapeutic success, but this problem is overcome with new-generation antisense molecules developed with chemical modifications. The types, carrier molecules, and gene regions targeted by sequences have been summarized in detail. Research and development of antisense therapy is still in its infancy; however, gene silencing therapies appear to have the potential for faster and longer-lasting activity than conventional treatment strategies. On the other hand, realizing the potential of antisense therapy will require a large initial economic investment to ascertain the pharmacological properties and learn how to optimize them. The ability of ASOs to be rapidly designed and synthesized to target different microbes can reduce drug discovery time from 6 years to 1 year. Since ASOs are not particularly affected by resistance mechanisms, they come to the fore in the fight against antimicrobial resistance. The design-based flexibility of ASOs has enabled it to be used for different types of microorganisms/genes and successful in vitro and in vivo results have been revealed. The current review summarized a comprehensive understanding of ASO therapy in combating bacterial and viral infections.
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Affiliation(s)
- Yamaç Tekintaş
- Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Izmir Katip Celebi University, Izmir, Türkiye
| | - Aybala Temel
- Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Izmir Katip Celebi University, Izmir, Türkiye
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Alishah Aratboni H, Rafiei N, Uscanga-Palomeque AC, Luna Cruz IE, Parra-Saldivar R, Morones-Ramirez JR. Design of a nanobiosystem with remote photothermal gene silencing in Chlamydomonas reinhardtii to increase lipid accumulation and production. Microb Cell Fact 2023; 22:61. [PMID: 37004064 PMCID: PMC10064687 DOI: 10.1186/s12934-023-02063-9] [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: 07/25/2022] [Accepted: 03/16/2023] [Indexed: 04/03/2023] Open
Abstract
Research development in the precise control of gene expression in plant cells is an emerging necessity that would lead to the elucidation of gene function in these biological systems. Conventional gene-interfering techniques, such as micro-RNA and short interfering RNA, have limitations in their ability to downregulate gene expression in plants within short time periods. However, nanotechnology provides a promising new avenue with new tools to overcome these challenges. Here, we show that functionalized gold nanoparticles, decorated with sense and antisense oligonucleotides (FANSAO), can serve as a remote-control optical switch for gene interference in photosynthetic plant cells. We demonstrate the potential of employing LEDs as optimal light sources to photothermally dehybridize the oligonucleotides on the surface of metallic nanostructures, consequently inducing regulation of gene expression in plant cells. We show the efficiency of metallic nanoparticles in absorbing light from an LED source and converting it to thermal energy, resulting in a local temperature increase on the surface of the gold nanoparticles. The antisense oligonucleotides are then released due to the opto-thermal heating of the nanobiosystem composed of the metallic nanoparticles and the sense-antisense oligonucleotides. By applying this approach, we silenced the Carnitine Acyl Carnitine Translocase genes at 90.7%, resulting in the accumulation of lipid bodies in microalgae cells. These results exhibit the feasibility of using functionalized gold nanoparticles with sense and antisense oligonucleotides to enhance nucleic acid delivery efficiency and, most importantly, allow for temporal control of gene silencing in plant cells. These nanobiosystems have broad applications in the development and biosynthesis of biofuels, pharmaceuticals, and specialized chemicals.
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Affiliation(s)
- Hossein Alishah Aratboni
- Universidad Autónoma de Nuevo León, UANL. Facultad de Ciencias Químicas, Av. Universidad S/N. CD. Universitaria, San Nicolás de los Garza, 66455, Nuevo León, México
- Centro de Investigación en Biotecnología Y Nanotecnología, Facultad de Ciencias Químicas, Parque de Investigación e Innovación Tecnológica, Universidad Autónoma de Nuevo León, Km. 10 Autopista Al Aeropuerto Internacional Mariano Escobedo, 66629, Apodaca, Nuevo León, México
| | - Nahid Rafiei
- Universidad Autónoma de Nuevo León, UANL. Facultad de Ciencias Químicas, Av. Universidad S/N. CD. Universitaria, San Nicolás de los Garza, 66455, Nuevo León, México
- Centro de Investigación en Biotecnología Y Nanotecnología, Facultad de Ciencias Químicas, Parque de Investigación e Innovación Tecnológica, Universidad Autónoma de Nuevo León, Km. 10 Autopista Al Aeropuerto Internacional Mariano Escobedo, 66629, Apodaca, Nuevo León, México
- Department of Plant Production and Genetics, School of Agriculture, Shiraz University, Km. 12 Shiraz-Isfahan Highway, Bajgah Area, Shiraz, 71441-65186, Iran
| | - Ashanti Concepción Uscanga-Palomeque
- Universidad Autónoma de Nuevo León, UANL. Facultad de Ciencias Químicas, Av. Universidad S/N. CD. Universitaria, San Nicolás de los Garza, 66455, Nuevo León, México
| | - Itza Eloisa Luna Cruz
- Universidad Autónoma de Nuevo León, UANL. Facultad de Ciencias Químicas, Av. Universidad S/N. CD. Universitaria, San Nicolás de los Garza, 66455, Nuevo León, México
| | - Roberto Parra-Saldivar
- School of Engineering and Sciences, Tecnologico de Monterrey, Ave. Eugenio Garza Sada 2501, CP 64849, Monterrey, NL, México
- Institute of Advanced Materials for Sustainable Manufacturing, Tecnologico de Monterrey, 64849, Monterrey, Nuevo Leon, Mexico
| | - Jose Ruben Morones-Ramirez
- Universidad Autónoma de Nuevo León, UANL. Facultad de Ciencias Químicas, Av. Universidad S/N. CD. Universitaria, San Nicolás de los Garza, 66455, Nuevo León, México.
- Centro de Investigación en Biotecnología Y Nanotecnología, Facultad de Ciencias Químicas, Parque de Investigación e Innovación Tecnológica, Universidad Autónoma de Nuevo León, Km. 10 Autopista Al Aeropuerto Internacional Mariano Escobedo, 66629, Apodaca, Nuevo León, México.
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Al-Absi MY, Caprifico AE, Calabrese G. Chitosan and Its Structural Modifications for siRNA Delivery. Adv Pharm Bull 2023; 13:275-282. [PMID: 37342385 PMCID: PMC10278227 DOI: 10.34172/apb.2023.030] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 12/18/2021] [Accepted: 01/07/2022] [Indexed: 07/30/2023] Open
Abstract
The use of RNA interference mechanism and small interfering RNA (siRNA) in cancer gene therapy is a very promising approach. However, the success of gene silencing is underpinned by the efficient delivery of intact siRNA into the targeted cell. Nowadays, chitosan is one of the most widely studied non-viral vectors for siRNA delivery, since it is a biodegradable, biocompatible and positively charged polymer able to bind to the negatively charged siRNA forming nanoparticles (NPs) that will act as siRNA delivery system. However, chitosan shows several limitations such as low transfection efficiency and low solubility at physiological pH. Therefore, a variety of chemical and non-chemical structural modifications of chitosan were investigated in the attempt to develop a chitosan derivative showing the features of an ideal siRNA carrier. In this review, the most recently proposed chemical modifications of chitosan are outlined. The type of modification, chemical structure, physicochemical properties, siRNA binding affinity and complexation efficiency of the modified chitosan are discussed. Moreover, the resulting NPs characteristics, cellular uptake, serum stability, cytotoxicity and gene transfection efficiency in vitro and/or in vivo are described and compared to the unmodified chitosan. Finally, a critical analysis of a selection of modifications is included, highlighting the most promising ones for this purpose in the future.
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Suppressing gain-of-function proteins via CRISPR/Cas9 system in SCA1 cells. Sci Rep 2022; 12:20285. [PMID: 36434031 PMCID: PMC9700751 DOI: 10.1038/s41598-022-24299-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 11/14/2022] [Indexed: 11/27/2022] Open
Abstract
SCAs are autosomal dominant neurodegenerative disorders caused by a gain-of-function protein with toxic activities, containing an expanded polyQ tract in the coding region. There are no treatments available to delay the onset, stop or slow down the progression of these pathologies. In this work we focus our attention on SCA1 which is one of the most common genotypes circulating in Italy. Here, we develop a CRISPR/Cas9-based approach to reduce both forms of the ATXN1 protein, normal and mutated with expanded polyQ. We started with the screening of 10 different sgRNAs able to target Exon 8 of the ATXN1 gene. The two most promising sgRNAs were validated in fibroblasts isolated from SCA1 patients, following the identification of the best transfection method for this type of cell. Our silencing approach significantly downregulated the expression of ataxin1, due to large deletions and the introduction of small changes in the ATXN1 gene, evidenced by NGS analysis, without major effects on cell viability. Furthermore, very few significant guide RNA-dependent off-target effects were observed. These preliminary results not only allowed us to identify the best transfection method for SCA1 fibroblasts, but strongly support CRISPR/Cas9 as a promising approach for the treatment of expanded polyQ diseases. Further investigations will be needed to verify the efficacy of our silencing system in SCA1 neurons and animal models.
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Viegas JSR, Bentley MVLB, Vicentini FTMDC. Challenges to perform an efficiently gene therapy adopting non-viral vectors: Melanoma landscape. J Drug Deliv Sci Technol 2022. [DOI: 10.1016/j.jddst.2022.103964] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Huang S, Hao XY, Li YJ, Wu JY, Xiang DX, Luo S. Nonviral delivery systems for antisense oligonucleotide therapeutics. Biomater Res 2022; 26:49. [PMID: 36180936 PMCID: PMC9523189 DOI: 10.1186/s40824-022-00292-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Accepted: 08/30/2022] [Indexed: 11/10/2022] Open
Abstract
Antisense oligonucleotides (ASOs) are an important tool for the treatment of many genetic disorders. However, similar to other gene drugs, vectors are often required to protect them from degradation and clearance, and to accomplish their transport in vivo. Compared with viral vectors, artificial nonviral nanoparticles have a variety of design, synthesis, and formulation possibilities that can be selected to accomplish protection and delivery for specific applications, and they have served critical therapeutic purposes in animal model research and clinical applications, allowing safe and efficient gene delivery processes into the target cells. We believe that as new ASO drugs develop, the exploration for corresponding nonviral vectors is inevitable. Intensive development of nonviral vectors with improved delivery strategies based on specific targets can continue to expand the value of ASO therapeutic approaches. Here, we provide an overview of current nonviral delivery strategies, including ASOs modifications, action mechanisms, and multi-carrier methods, which aim to address the irreplaceable role of nonviral vectors in the progressive development of ASOs delivery.
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Affiliation(s)
- Si Huang
- Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, 410011, People's Republic of China.,Hunan Provincial Engineering Research Centre of Translational Medicine and Innovative Drug, Changsha, 410011, People's Republic of China.,Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Xin-Yan Hao
- Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, 410011, People's Republic of China.,Hunan Provincial Engineering Research Centre of Translational Medicine and Innovative Drug, Changsha, 410011, People's Republic of China.,Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Yong-Jiang Li
- Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, 410011, People's Republic of China.,Hunan Provincial Engineering Research Centre of Translational Medicine and Innovative Drug, Changsha, 410011, People's Republic of China.,Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Jun-Yong Wu
- Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, 410011, People's Republic of China.,Hunan Provincial Engineering Research Centre of Translational Medicine and Innovative Drug, Changsha, 410011, People's Republic of China.,Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Da-Xiong Xiang
- Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, 410011, People's Republic of China.,Hunan Provincial Engineering Research Centre of Translational Medicine and Innovative Drug, Changsha, 410011, People's Republic of China.,Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Shilin Luo
- Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, 410011, People's Republic of China. .,Hunan Provincial Engineering Research Centre of Translational Medicine and Innovative Drug, Changsha, 410011, People's Republic of China. .,Institute of Clinical Pharmacy, Central South University, Changsha, China.
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Internal Ribosome Entry Site (IRES)-Mediated Translation and Its Potential for Novel mRNA-Based Therapy Development. Biomedicines 2022; 10:biomedicines10081865. [PMID: 36009412 PMCID: PMC9405587 DOI: 10.3390/biomedicines10081865] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 07/26/2022] [Accepted: 07/29/2022] [Indexed: 11/17/2022] Open
Abstract
Many conditions can benefit from RNA-based therapies, namely, those targeting internal ribosome entry sites (IRESs) and their regulatory proteins, the IRES trans-acting factors (ITAFs). IRES-mediated translation is an alternative mechanism of translation initiation, known for maintaining protein synthesis when canonical translation is impaired. During a stress response, it contributes to cell reprogramming and adaptation to the new environment. The relationship between IRESs and ITAFs with tumorigenesis and resistance to therapy has been studied in recent years, proposing new therapeutic targets and treatments. In addition, IRES-dependent translation initiation dysregulation is also related to neurological and cardiovascular diseases, muscular atrophies, or other syndromes. The participation of these structures in the development of such pathologies has been studied, yet to a far lesser extent than in cancer. Strategies involving the disruption of IRES–ITAF interactions or the modification of ITAF expression levels may be used with great impact in the development of new therapeutics. In this review, we aim to comprehend the current data on groups of human pathologies associated with IRES and/or ITAF dysregulation and their application in the designing of new therapeutic approaches using them as targets or tools. Thus, we wish to summarise the evidence in the field hoping to open new promising lines of investigation toward personalised treatments.
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Lange J, Zhou H, McTague A. Cerebral Organoids and Antisense Oligonucleotide Therapeutics: Challenges and Opportunities. Front Mol Neurosci 2022; 15:941528. [PMID: 35836547 PMCID: PMC9274522 DOI: 10.3389/fnmol.2022.941528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 06/09/2022] [Indexed: 11/18/2022] Open
Abstract
The advent of stem cell-derived cerebral organoids has already advanced our understanding of disease mechanisms in neurological diseases. Despite this, many remain without effective treatments, resulting in significant personal and societal health burden. Antisense oligonucleotides (ASOs) are one of the most widely used approaches for targeting RNA and modifying gene expression, with significant advancements in clinical trials for epilepsy, neuromuscular disorders and other neurological conditions. ASOs have further potential to address the unmet need in other neurological diseases for novel therapies which directly target the causative genes, allowing precision treatment. Induced pluripotent stem cell (iPSC) derived cerebral organoids represent an ideal platform in which to evaluate novel ASO therapies. In patient-derived organoids, disease-causing mutations can be studied in the native genetic milieu, opening the door to test personalized ASO therapies and n-of-1 approaches. In addition, CRISPR-Cas9 can be used to generate isogenic iPSCs to assess the effects of ASOs, by either creating disease-specific mutations or correcting available disease iPSC lines. Currently, ASO therapies face a number of challenges to wider translation, including insufficient uptake by distinct and preferential cell types in central nervous system and inability to cross the blood brain barrier necessitating intrathecal administration. Cerebral organoids provide a practical model to address and improve these limitations. In this review we will address the current use of organoids to test ASO therapies, opportunities for future applications and challenges including those inherent to cerebral organoids, issues with organoid transfection and choice of appropriate read-outs.
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Affiliation(s)
- Jenny Lange
- Department for Developmental Neurosciences, Zayed Centre for Research Into Rare Disease in Children, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
| | - Haiyan Zhou
- Genetics and Genomic Medicine Research and Teaching Department, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
- NIHR Great Ormond Street Hospital Biomedical Research Centre, London, United Kingdom
| | - Amy McTague
- Department for Developmental Neurosciences, Zayed Centre for Research Into Rare Disease in Children, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
- NIHR Great Ormond Street Hospital Biomedical Research Centre, London, United Kingdom
- *Correspondence: Amy McTague,
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Dormancy in Breast Cancer, the Role of Autophagy, lncRNAs, miRNAs and Exosomes. Int J Mol Sci 2022; 23:ijms23095271. [PMID: 35563661 PMCID: PMC9105119 DOI: 10.3390/ijms23095271] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Revised: 05/04/2022] [Accepted: 05/06/2022] [Indexed: 12/04/2022] Open
Abstract
Breast cancer (BC) is the most frequently diagnosed cancer in women for which numerous diagnostic and therapeutic options have been developed. Namely, the targeted treatment of BC, for the most part, relies on the expression of growth factors and hormone receptors by these cancer cells. Despite this, close to 30% of BC patients may experience relapse due to the presence of minimal residual disease (MRD) consisting of surviving disseminated tumour cells (DTCs) from the primary tumour which can colonise a secondary site. This can lead to either detectable metastasis or DTCs entering a dormant state for a prolonged period where they are undetectable. In the latter, cells can re-emerge from their dormant state due to intrinsic and microenvironmental cues leading to relapse and metastatic outgrowth. Pre- and clinical studies propose that targeting dormant DTCs may inhibit metastasis, but the choice between keeping them dormant or forcing their “awakening” is still controversial. This review will focus on cancer cells’ microenvironmental cues and metabolic and molecular properties, which lead to dormancy, relapse, and metastatic latency in BC. Furthermore, we will focus on the role of autophagy, long non-coding RNAs (lncRNAs), miRNAs, and exosomes in influencing the induction of dormancy and awakening of dormant BC cells. In addition, we have analysed BC treatment from a viewpoint of autophagy, lncRNAs, miRNAs, and exosomes. We propose the targeted modulation of these processes and molecules as modern aspects of precision medicine for BC treatment, improving both novel and traditional BC treatment options. Understanding these pathways and processes may ultimately improve BC patient prognosis, patient survival, and treatment response.
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50
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Peng B, Nguyen TM, Jayasinghe MK, Gao C, Pham TT, Vu LT, Yeo EYM, Yap G, Wang L, Goh BC, Tam WL, Luo D, Le MTN. Robust delivery of RIG-I agonists using extracellular vesicles for anti-cancer immunotherapy. J Extracell Vesicles 2022; 11:e12187. [PMID: 35430766 PMCID: PMC9013404 DOI: 10.1002/jev2.12187] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 11/29/2021] [Accepted: 01/05/2022] [Indexed: 01/23/2023] Open
Abstract
The RIG-I pathway can be activated by RNA containing 5' triphosphate, leading to type I interferon release and immune activation. Hence, RIG-I agonists have been used to induce immune responses against cancer as potential immunotherapy. However, delivery of 5' triphosphorylated RNA molecules as RIG-I agonists to tumour cells in vivo is challenging due to the susceptibility of these molecules to degradation. In this study, we demonstrate the use of extracellular vesicles (EVs) from red blood cells (RBCs), which are highly amenable for RNA loading and taken up robustly by cancer cells, for RIG-I agonist delivery. We evaluate the anti-cancer activity of two novel RIG-I agonists, the immunomodulatory RNA (immRNA) with a unique secondary structure for efficient RIG-I activation, and a 5' triphosphorylated antisense oligonucleotide with dual function of RIG-I activation and miR-125b inhibition (3p-125b-ASO). We find that RBCEV-delivered immRNA and 3p-125b-ASO trigger the RIG-I pathway, and induce cell death in both mouse and human breast cancer cells. Furthermore, we observe a significant suppression of tumour growth coupled with increased immune cell infiltration mediated by the activation of RIG-I cascade after multiple intratumoral injections of RBCEVs loaded with immRNA or 3p-125b-ASO. Targeted delivery of immRNA using RBCEVs with EGFR-binding nanobody administrated via intrapulmonary delivery facilitates the accumulation of RBCEVs in metastatic cancer cells, leading to potent tumour-specific CD8+ T cells immune response. This contributes to prominent suppression of breast cancer metastasis in the lung. Hence, this study provides a new strategy for efficient RIG-I agonist delivery using RBCEVs for immunotherapy against cancer and cancer metastasis.
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Affiliation(s)
- Boya Peng
- Department of Pharmacology and Institute for Digital MedicineYong Loo Lin School of MedicineNational University of SingaporeSingapore
- Department of SurgeryImmunology ProgramCancer Program and Nanomedicine Translational ProgramYong Loo Lin School of MedicineNational University of SingaporeSingapore
| | - Trinh Mai Nguyen
- Lee Kong Chian School of MedicineNanyang Technological UniversitySingapore
- NTU Institute of Structural BiologyNanyang Technological UniversitySingapore
| | - Migara Kavishka Jayasinghe
- Department of Pharmacology and Institute for Digital MedicineYong Loo Lin School of MedicineNational University of SingaporeSingapore
- Department of SurgeryImmunology ProgramCancer Program and Nanomedicine Translational ProgramYong Loo Lin School of MedicineNational University of SingaporeSingapore
| | - Chang Gao
- Department of Pharmacology and Institute for Digital MedicineYong Loo Lin School of MedicineNational University of SingaporeSingapore
- Department of SurgeryImmunology ProgramCancer Program and Nanomedicine Translational ProgramYong Loo Lin School of MedicineNational University of SingaporeSingapore
| | - Thach Tuan Pham
- Department of Pharmacology and Institute for Digital MedicineYong Loo Lin School of MedicineNational University of SingaporeSingapore
- Department of SurgeryImmunology ProgramCancer Program and Nanomedicine Translational ProgramYong Loo Lin School of MedicineNational University of SingaporeSingapore
| | - Luyen Tien Vu
- Department of Pharmacology and Institute for Digital MedicineYong Loo Lin School of MedicineNational University of SingaporeSingapore
- Department of SurgeryImmunology ProgramCancer Program and Nanomedicine Translational ProgramYong Loo Lin School of MedicineNational University of SingaporeSingapore
| | - Eric Yew Meng Yeo
- Department of Pharmacology and Institute for Digital MedicineYong Loo Lin School of MedicineNational University of SingaporeSingapore
- Department of SurgeryImmunology ProgramCancer Program and Nanomedicine Translational ProgramYong Loo Lin School of MedicineNational University of SingaporeSingapore
| | - Gracemary Yap
- Department of Pharmacology and Institute for Digital MedicineYong Loo Lin School of MedicineNational University of SingaporeSingapore
- Department of SurgeryImmunology ProgramCancer Program and Nanomedicine Translational ProgramYong Loo Lin School of MedicineNational University of SingaporeSingapore
| | - Lingzhi Wang
- Cancer Science Institute of SingaporeNational University of SingaporeSingapore
| | - Boon Cher Goh
- Cancer Science Institute of SingaporeNational University of SingaporeSingapore
| | - Wai Leong Tam
- Cancer Science Institute of SingaporeNational University of SingaporeSingapore
- Genome Institute of Singapore, A*STARSingapore
| | - Dahai Luo
- Lee Kong Chian School of MedicineNanyang Technological UniversitySingapore
- NTU Institute of Structural BiologyNanyang Technological UniversitySingapore
| | - Minh TN Le
- Department of Pharmacology and Institute for Digital MedicineYong Loo Lin School of MedicineNational University of SingaporeSingapore
- Department of SurgeryImmunology ProgramCancer Program and Nanomedicine Translational ProgramYong Loo Lin School of MedicineNational University of SingaporeSingapore
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