Comprehensive review of adverse reactions and toxicology in ASO-based therapies for Duchenne Muscular Dystrophy: From FDA-approved drugs to peptide-conjugated ASO
Duchenne Muscular Dystrophy (DMD) is a devastating X-linked genetic disorder characterized by progressive muscle degeneration due to mutations in the dystrophin gene. This results in the absence or dysfunction of the dystrophin protein, leading to muscle weakness, loss of ambulation, respiratory iss...
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Elsevier
2024-01-01
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| Series: | Current Research in Toxicology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666027X24000355 |
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| author | Umme Sabrina Haque Melissa Kohut Toshifumi Yokota |
| author_facet | Umme Sabrina Haque Melissa Kohut Toshifumi Yokota |
| author_sort | Umme Sabrina Haque |
| collection | DOAJ |
| description | Duchenne Muscular Dystrophy (DMD) is a devastating X-linked genetic disorder characterized by progressive muscle degeneration due to mutations in the dystrophin gene. This results in the absence or dysfunction of the dystrophin protein, leading to muscle weakness, loss of ambulation, respiratory issues, and cardiac complications, often leading to premature death. Recently, antisense oligonucleotide (ASO)-mediated exon skipping has emerged as a promising therapeutic strategy for DMD. Notably, the FDA has conditionally approved four ASO therapies for DMD, with numerous others in various stages of clinical development, indicating the growing interest and potential in this field. To enhance ASO-based therapies, researchers have explored the novel concept of conjugating peptides to the phosphorodiamidate morpholino backbone (PMO) of ASOs, leading to the development of peptide-conjugated PMOs (PPMOs). These PPMOs have demonstrated significantly improved pharmacokinetic profiles, potentially augmenting their therapeutic effectiveness. Despite the optimism surrounding ASOs and PPMOs, concerns persist regarding their efficacy and safety. To comprehensively evaluate these therapies, it is imperative to expand patient populations in clinical trials and conduct thorough investigations into the associated risks. This article provides a comprehensive review and discussion of the available data pertaining to adverse reactions and toxicology associated with FDA-approved ASO drugs for DMD. Furthermore, it offers insights into the emerging category of peptide-conjugated ASO drugs those are clinical and preclinical trials, shedding light on their potential benefits and challenges. |
| format | Article |
| id | doaj-art-4bc8b59de5f7483da8fd0386aaf8f26c |
| institution | Kabale University |
| issn | 2666-027X |
| language | English |
| publishDate | 2024-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Current Research in Toxicology |
| spelling | doaj-art-4bc8b59de5f7483da8fd0386aaf8f26c2024-12-14T06:32:52ZengElsevierCurrent Research in Toxicology2666-027X2024-01-017100182Comprehensive review of adverse reactions and toxicology in ASO-based therapies for Duchenne Muscular Dystrophy: From FDA-approved drugs to peptide-conjugated ASOUmme Sabrina Haque0Melissa Kohut1Toshifumi Yokota2Department of Neuroscience, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada; Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, CanadaDepartment of Neuroscience, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada; Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, CanadaDepartment of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada; The Friends of Garrett Cumming Research & Muscular Dystrophy Canada HM Toupin Neurological Science Research, Edmonton, AB T6G 2H7, Canada; Corresponding author.Duchenne Muscular Dystrophy (DMD) is a devastating X-linked genetic disorder characterized by progressive muscle degeneration due to mutations in the dystrophin gene. This results in the absence or dysfunction of the dystrophin protein, leading to muscle weakness, loss of ambulation, respiratory issues, and cardiac complications, often leading to premature death. Recently, antisense oligonucleotide (ASO)-mediated exon skipping has emerged as a promising therapeutic strategy for DMD. Notably, the FDA has conditionally approved four ASO therapies for DMD, with numerous others in various stages of clinical development, indicating the growing interest and potential in this field. To enhance ASO-based therapies, researchers have explored the novel concept of conjugating peptides to the phosphorodiamidate morpholino backbone (PMO) of ASOs, leading to the development of peptide-conjugated PMOs (PPMOs). These PPMOs have demonstrated significantly improved pharmacokinetic profiles, potentially augmenting their therapeutic effectiveness. Despite the optimism surrounding ASOs and PPMOs, concerns persist regarding their efficacy and safety. To comprehensively evaluate these therapies, it is imperative to expand patient populations in clinical trials and conduct thorough investigations into the associated risks. This article provides a comprehensive review and discussion of the available data pertaining to adverse reactions and toxicology associated with FDA-approved ASO drugs for DMD. Furthermore, it offers insights into the emerging category of peptide-conjugated ASO drugs those are clinical and preclinical trials, shedding light on their potential benefits and challenges.http://www.sciencedirect.com/science/article/pii/S2666027X24000355DMDEteplirsenGolodirsenViltolarsenCasimersenSRP-5051 |
| spellingShingle | Umme Sabrina Haque Melissa Kohut Toshifumi Yokota Comprehensive review of adverse reactions and toxicology in ASO-based therapies for Duchenne Muscular Dystrophy: From FDA-approved drugs to peptide-conjugated ASO Current Research in Toxicology DMD Eteplirsen Golodirsen Viltolarsen Casimersen SRP-5051 |
| title | Comprehensive review of adverse reactions and toxicology in ASO-based therapies for Duchenne Muscular Dystrophy: From FDA-approved drugs to peptide-conjugated ASO |
| title_full | Comprehensive review of adverse reactions and toxicology in ASO-based therapies for Duchenne Muscular Dystrophy: From FDA-approved drugs to peptide-conjugated ASO |
| title_fullStr | Comprehensive review of adverse reactions and toxicology in ASO-based therapies for Duchenne Muscular Dystrophy: From FDA-approved drugs to peptide-conjugated ASO |
| title_full_unstemmed | Comprehensive review of adverse reactions and toxicology in ASO-based therapies for Duchenne Muscular Dystrophy: From FDA-approved drugs to peptide-conjugated ASO |
| title_short | Comprehensive review of adverse reactions and toxicology in ASO-based therapies for Duchenne Muscular Dystrophy: From FDA-approved drugs to peptide-conjugated ASO |
| title_sort | comprehensive review of adverse reactions and toxicology in aso based therapies for duchenne muscular dystrophy from fda approved drugs to peptide conjugated aso |
| topic | DMD Eteplirsen Golodirsen Viltolarsen Casimersen SRP-5051 |
| url | http://www.sciencedirect.com/science/article/pii/S2666027X24000355 |
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