Innovative Therapeutic Approaches for Duchenne Muscular Dystrophy
Abstract
:1. Introduction
2. Molecular Genetics of DMD
3. Pathophysiology of DMD
3.1. Striated Muscle
3.2. Brain
4. Rationale for Current Therapeutic Interventions in DMD
4.1. Restoring Dystrophin Protein Production
4.2. Ataluren as a Read-Through Strategy for Nonsense Mutations
4.3. AAV Gene Therapy
4.4. Future Perspectives
4.4.1. CRISPR/Cas9 Mediated Gene Editing
4.4.2. Stem Cell Therapy
5. Conclusions and Future Directions
Author Contributions
Funding
Conflicts of Interest
References
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Chemical Modification | Therapeutic Molecule | Company | Skipped Exon | Clinical Trial | Phase | Duration |
---|---|---|---|---|---|---|
Phosphorodi-amidate morpholino oligomers (PMO) | Eteplirsen | Sarepta Ther. | Exon 51 | NCT03218995 NCT04179409 NCT03992430 NCT03985878 | Phase 2 Phase 2 Phase 3 Phase 2 | 2017–2021 2020–2022 2020–2026 2019–2027 |
Golodirsen | Sarepta Ther. | Exon 53 | NCT04179409 NCT02500381 NCT03532542 | Phase 2 Phase 3 Phase 3 | 2020–2022 2016–2023 2018–2026 | |
Casimersen | Sarepta Ther. | Exon 45 | NCT04179409 NCT03532542 | Phase 2 Phase 3 | 2020–2022 2018–2026 | |
Viltolarsen | NS Pharma, Inc. | Exon 53 | NCT03167255 NCT04060199 | Phase 2 Phase 3 | 2017–2021 2020–2024 | |
2′-O-Methyl-phosphorothioates (2’OMePS) | Drisapersen | BioMarin Pharmaceutical | Exon 51 | NCT02636686 | Phase 3 | 2015–2018 |
DS-5141b | Daiichi Sankyo Co., Ltd. | Exon 45 | NCT04433234 | Phase 2 | 2020–2022 | |
Peptide phosphorodiamidate morpholino oligomer (PPMO) | SRP-5051 | Sarepta Ther. | Exon 51 | NCT03675126 NCT04004065 | Phase 1/2 Phase 2 | 2018–2024 2019–2022 |
Stereopure | Suvodirsen | Wave Life Sciences Ltd. | Exon 51 | NCT03907072 | Phase 2/3 | 2019–2020 |
Name | Chemical modification | Properties |
---|---|---|
Phosphorodiamidate morpholino oligomers (PMO) |
| Advantages
|
Peptide phosphorodiamidate morpholino oligomer (PPMO) | Conjugation with the cell-penetrating peptide (CPP) | Advantages
Nephrotoxicity correlated with arginine content of the CPP |
2’-O-methyl-phosphorothioates (2’OMePS) |
| Advantages
Toxicity and adverse effects due to retention in the kidneys and liver |
Stereopure 2’OMePS | Stereochemical and chemical purity (defined stereochemistry at each PS linkage) | Advantages
No induction of dystrophin expression in vivo |
Sponsor | Clinical Trials. Gov Identifier | Trial Name | Study Phase | Drug Name | AAV-Serotype | Primary Outcome | Secondary Outcome | Side Effects |
---|---|---|---|---|---|---|---|---|
Solid Biosciences, LLC | NCT03368742 | Micro-dystrophin Gene Transfer Study in Adolescents and Children With DMD (IGNITE DMD) | Phase I and II, open-label, randomized, controlled | SGT-001 | AAV-9 Muscle (skeletal and cardiac) tissue tropism | Safety and microdystrophin expression in biopsy | / | A serious adverse event (SAE) characterized by complement activation, thrombocytopenia, a decrease in red blood cell count, acute kidney injury, and cardio-pulmonary insufficiency |
Sarepta Therapeutics, Inc. | NCT03375164 | Systemic Gene Delivery Clinical Trial for Duchenne Muscular Dystrophy (DMD) | Phase I and II, open-label, non-randomized | rAAVrh74.MHCK7. Micro-dystrophin | AAV-rh74 Muscle (skeletal and cardiac) tissue tropism | Safety | Microdystrophin expression in biopsy and motor performances | No SAEs; Adverse events reported: elevated γ-glutamil transpeptidase; transient nausea |
Pfizer | NCT03362502 | A Study to Evaluate the Safety and Tolerability of PF-06939926 Gene Therapy in Duchenne Muscular Dystrophy | Phase Ib, open-label, non-randomized | PF-06939926 | AAV-9 Muscle (skeletal and cardiac) tissue tropism | Safety and tolerability | Micro-dystrophin expression in biopsy | Three SAEs fully recovered: persistent vomiting; acute kidney injury with atypical hemolytic uremic syndrome (aHUS)-like complement activation; thrombocytopenia with aHUS-like complement activation |
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Fortunato, F.; Rossi, R.; Falzarano, M.S.; Ferlini, A. Innovative Therapeutic Approaches for Duchenne Muscular Dystrophy. J. Clin. Med. 2021, 10, 820. https://doi.org/10.3390/jcm10040820
Fortunato F, Rossi R, Falzarano MS, Ferlini A. Innovative Therapeutic Approaches for Duchenne Muscular Dystrophy. Journal of Clinical Medicine. 2021; 10(4):820. https://doi.org/10.3390/jcm10040820
Chicago/Turabian StyleFortunato, Fernanda, Rachele Rossi, Maria Sofia Falzarano, and Alessandra Ferlini. 2021. "Innovative Therapeutic Approaches for Duchenne Muscular Dystrophy" Journal of Clinical Medicine 10, no. 4: 820. https://doi.org/10.3390/jcm10040820
APA StyleFortunato, F., Rossi, R., Falzarano, M. S., & Ferlini, A. (2021). Innovative Therapeutic Approaches for Duchenne Muscular Dystrophy. Journal of Clinical Medicine, 10(4), 820. https://doi.org/10.3390/jcm10040820