Therapeutic Strategies for Duchenne Muscular Dystrophy: An Update
Abstract
:1. Introduction
2. Genetic Pathogenesis of DMD
2.1. An Overview of Dystrophin Gene Mutations—Types and Sites
2.2. Correlation between Mutations and Disease Severity
2.3. Diagnosis Techniques Targeting Mutated Exons
3. Stem Cell-Related DMD Pathogenesis
4.1. Read-Through Therapy
4.1.1. Antibiotics and Synthetic Analogues that Mediate Stop-Codon Read-Through
4.1.2. Ataluren-Mediated Stop-Codon Read-Through
4.2. AON-Mediated Exon Skip** Therapy
4.2.1. Phosphorodiamidate Morpholino Oligomer (PMO) Modification
4.2.2. 2′-O-Methyl-Phosphorothioate (2′OMePS) Modification
4.2.3. Peptide-Conjugated PMO (PPMO)
4.2.4. Stereopure AON
4.2.5. Efficacy and Safety of AON-Mediated Exon Skip**
4.3. Vector-Mediated Gene Therapy
4.3.1. AAV-Mediated Mini-/Microdystrophin Transfer
4.3.2. Artificial Chromosome-Mediated Dystrophin Transfer
4.4. CRISPR/Cas9-Mediated Gene Editing
4.4.1. Ex Vivo CRISPR/Cas9 Gene Editing
4.4.2. In Vivo CRISPR/Cas9 Gene Editing
4.5. Exogenous Cell Transplantation
4.6. Level of Functional Dystrophin Required for Clinical Efficacy
5. Discussion and Future Direction
Author Contributions
Funding
Conflicts of Interest
References
- Kolwicz, S.C., Jr.; Hall, J.K.; Moussavi-Harami, F.; Chen, X.; Hauschka, S.D.; Chamberlain, J.S.; Regnier, M.; Odom, G.L. Gene Therapy Rescues Cardiac Dysfunction in Duchenne Muscular Dystrophy Mice by Elevating Cardiomyocyte Deoxy-Adenosine Triphosphate. JACC Basic Transl. Sci. 2019, 4, 778–791. [Google Scholar] [CrossRef] [PubMed]
- Verhaart, I.E.C.; Aartsma-Rus, A. Therapeutic developments for Duchenne muscular dystrophy. Nat. Rev. Neurol. 2019, 15, 373–386. [Google Scholar] [CrossRef] [PubMed]
- Koenig, M.; Monaco, A.P.; Kunkel, L.M. The complete sequence of dystrophin predicts a rod-shaped cytoskeletal protein. Cell 1988, 53, 219–228. [Google Scholar] [CrossRef]
- Salmaninejad, A.; Jafari Abarghan, Y.; Bozorg Qomi, S.; Bayat, H.; Yousefi, M.; Azhdari, S.; Talebi, S.; Mojarrad, M. Common therapeutic advances for Duchenne muscular dystrophy (DMD). Int. J. Neurosci. 2020, 1–20. [Google Scholar] [CrossRef] [PubMed]
- Salmaninejad, A.; Valilou, S.F.; Bayat, H.; Ebadi, N.; Daraei, A.; Yousefi, M.; Nesaei, A.; Mojarrad, M. Duchenne muscular dystrophy: An updated review of common available therapies. Int. J. Neurosci. 2018, 128, 854–864. [Google Scholar] [CrossRef]
- Matre, P.R.; Mu, X.; Wu, J.; Danila, D.; Hall, M.A.; Kolonin, M.G.; Darabi, R.; Huard, J. CRISPR/Cas9-Based Dystrophin Restoration Reveals a Novel Role for Dystrophin in Bioenergetics and Stress Resistance of Muscle Progenitors. Stem Cells 2019, 37, 1615–1628. [Google Scholar] [CrossRef] [Green Version]
- Min, Y.L.; Bassel-Duby, R.; Olson, E.N. CRISPR Correction of Duchenne Muscular Dystrophy. Annu. Rev. Med. 2019, 70, 239–255. [Google Scholar] [CrossRef]
- Bladen, C.L.; Salgado, D.; Monges, S.; Foncuberta, M.E.; Kekou, K.; Kosma, K.; Dawkins, H.; Lamont, L.; Roy, A.J.; Chamova, T.; et al. The TREAT-NMD DMD Global Database: Analysis of More than 7000 Duchenne Muscular Dystrophy Mutations. Hum. Mutat. 2015, 36, 395–402. [Google Scholar] [CrossRef]
- Aartsma-Rus, A.; Van Deutekom, J.C.T.; Fokkema, I.F.; Van Ommen, G.-J.B.; Den Dunnen, J.T. Entries in the Leiden Duchenne muscular dystrophy mutation database: An overview of mutation types and paradoxical cases that confirm the reading-frame rule. Muscle Nerve 2006, 34, 135–144. [Google Scholar] [CrossRef]
- Koenig, M.; Beggs, A.H.; Moyer, M.; Scherpf, S.; Heindrich, K.; Bettecken, T.; Meng, G.; Müller, C.R.; Lindlöf, M.; Kaariainen, H.; et al. The molecular basis for Duchenne versus Becker muscular dystrophy: Correlation of severity with type of deletion. Am. J. Hum. Genet. 1989, 45, 498–506. [Google Scholar]
- Le Rumeur, E. Dystrophin and the two related genetic diseases, Duchenne and Becker muscular dystrophies. Bosn. J. Basic Med. Sci. 2015, 15, 14–20. [Google Scholar] [CrossRef] [Green Version]
- Zhang, K.; Yang, X.; Lin, G.; Han, Y.; Li, J. Molecular genetic testing and diagnosis strategies for dystrophinopathies in the era of next generation sequencing. Clin. Chim. Acta 2019, 491, 66–73. [Google Scholar] [CrossRef] [PubMed]
- Heald, A.; Anderson, L.V.; Bushby, K.M.; Shaw, P.J. Becker muscular dystrophy with onset after 60 years. Neurology 1994, 44, 2388–2390. [Google Scholar] [CrossRef] [PubMed]
- Mias-Lucquin, D.; Dos Santos Morais, R.; Chéron, A.; Lagarrigue, M.; Winder, S.J.; Chenuel, T.; Pérez, J.; Appavou, M.S.; Martel, A.; Alviset, G.; et al. How the central domain of dystrophin acts to bridge F-actin to sarcolemmal lipids. J. Struct. Biol. 2020, 209, 107411. [Google Scholar] [CrossRef] [PubMed]
- Kyrychenko, V.; Kyrychenko, S.; Tiburcy, M.; Shelton, J.M.; Long, C.; Schneider, J.W.; Zimmermann, W.H.; Bassel-Duby, R.; Olson, E.N. Functional correction of dystrophin actin binding domain mutations by genome editing. JCI Insight 2017, 2. [Google Scholar] [CrossRef] [PubMed]
- Kong, X.; Zhong, X.; Liu, L.; Cui, S.; Yang, Y.; Kong, L. Genetic analysis of 1051 Chinese families with Duchenne/Becker Muscular Dystrophy. BMC Med. Genet. 2019, 20, 139. [Google Scholar] [CrossRef] [Green Version]
- Vieitez, I.; Gallano, P.; Gonzalez-Quereda, L.; Borrego, S.; Marcos, I.; Millan, J.M.; Jairo, T.; Prior, C.; Molano, J.; Trujillo-Tiebas, M.J.; et al. Mutational spectrum of Duchenne muscular dystrophy in Spain: Study of 284 cases. Neurologia 2017, 32, 377–385. [Google Scholar] [CrossRef]
- Neri, M.; Rossi, R.; Trabanelli, C.; Mauro, A.; Selvatici, R.; Falzarano, M.S.; Spedicato, N.; Margutti, A.; Rimessi, P.; Fortunato, F.; et al. The Genetic Landscape of Dystrophin Mutations in Italy: A Nationwide Study. Front. Genet. 2020, 11, 131. [Google Scholar] [CrossRef]
- Aartsma-Rus, A.; Ginjaar, I.B.; Bushby, K. The importance of genetic diagnosis for Duchenne muscular dystrophy. J. Med. Genet. 2016, 53, 145. [Google Scholar] [CrossRef]
- Lalic, T.; Vossen, R.H.A.M.; Coffa, J.; Schouten, J.P.; Guc-Scekic, M.; Radivojevic, D.; Djurisic, M.; Breuning, M.H.; White, S.J.; den Dunnen, J.T. Deletion and duplication screening in the DMD gene using MLPA. Eur. J. Hum. Genet. 2005, 13, 1231–1234. [Google Scholar] [CrossRef]
- Varga, R.-E.; Mumtaz, R.; Jahic, A.; Rudenskaya, G.E.; Sánchez-Ferrero, E.; Auer-Grumbach, M.; Hübner, C.A.; Beetz, C. MLPA-based evidence for sequence gain: Pitfalls in confirmation and necessity for exclusion of false positives. Anal. Biochem. 2012, 421, 799–801. [Google Scholar] [CrossRef] [PubMed]
- Bovolenta, M.; Neri, M.; Fini, S.; Fabris, M.; Trabanelli, C.; Venturoli, A.; Martoni, E.; Bassi, E.; Spitali, P.; Brioschi, S.; et al. A novel custom high density-comparative genomic hybridization array detects common rearrangements as well as deep intronic mutations in dystrophinopathies. BMC Genom. 2008, 9, 572. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tanveer, N.; Sharma, M.C.; Sarkar, C.; Gulati, S.; Kalra, V.; Singh, S.; Bhatia, R. Diagnostic utility of skin biopsy in dystrophinopathies. Clin. Neurol. Neurosurg. 2009, 111, 496–502. [Google Scholar] [CrossRef] [PubMed]
- Iskandar, K.; Dwianingsih, E.K.; Pratiwi, L.; Kalim, A.S.; Mardhiah, H.; Putranti, A.H.; Nurputra, D.K.; Triono, A.; Herini, E.S.; Malueka, R.G.; et al. The analysis of DMD gene deletions by multiplex PCR in Indonesian DMD/BMD patients: The era of personalized medicine. BMC Res. Notes 2019, 12, 704. [Google Scholar] [CrossRef] [Green Version]
- Xu, Y.; Wang, H.; ** therapy. J. Hum. Genet. 2016, 61, 663–667. [Google Scholar] [CrossRef] [PubMed]
- Madaro, L.; Torcinaro, A.; De Bardi, M.; Contino, F.F.; Pelizzola, M.; Diaferia, G.R.; Imeneo, G.; Bouche, M.; Puri, P.L.; De Santa, F. Macrophages fine tune satellite cell fate in dystrophic skeletal muscle of mdx mice. PLoS Genet. 2019, 15, e1008408. [Google Scholar] [CrossRef] [PubMed]
- ** Therapies for Duchenne Muscular Dystrophy: A Critical Review and a Perspective on the Outstanding Issues. Nucleic Acid Ther. 2017, 27, 251–259. [Google Scholar] [CrossRef] [PubMed]
- Asher, D.R.; Thapa, K.; Dharia, S.D.; Khan, N.; Potter, R.A.; Rodino-Klapac, L.R.; Mendell, J.R. Clinical development on the frontier: Gene therapy for duchenne muscular dystrophy. Expert Opin. Biol. Ther. 2020, 20, 263–274. [Google Scholar] [CrossRef]
- Muntoni, F.; Wood, M.J.A. Targeting RNA to treat neuromuscular disease. Nat. Rev. Drug Discov. 2011, 10, 621–637. [Google Scholar] [CrossRef]
- Shimizu-Motohashi, Y.; Komaki, H.; Motohashi, N.; Takeda, S.I.; Yokota, T.; Aoki, Y. Restoring Dystrophin Expression in Duchenne Muscular Dystrophy: Current Status of Therapeutic Approaches. J. Pers. Med. 2019, 9, 1. [Google Scholar] [CrossRef] [Green Version]
- Moulton, H.M.; Moulton, J.D. Morpholinos and their peptide conjugates: Therapeutic promise and challenge for Duchenne muscular dystrophy. Biochim. Biophys. Acta 2010, 1798, 2296–2303. [Google Scholar] [CrossRef] [Green Version]
- Lu, Q.-L.; Yokota, T.; Takeda, S.I.; Garcia, L.; Muntoni, F.; Partridge, T. The status of exon skip** as a therapeutic approach to duchenne muscular dystrophy. Mol. Ther. J. Am. Soc. Gene Ther. 2011, 19, 9–15. [Google Scholar] [CrossRef]
- Yokota, T.; Lu, Q.-L.; Partridge, T.; Kobayashi, M.; Nakamura, A.; Takeda, S.; Hoffman, E. Efficacy of systemic morpholino exon-skip** in duchenne dystrophy dogs. Ann. Neurol. 2009, 65, 667–676. [Google Scholar] [CrossRef]
- Aoki, Y.; Nakamura, A.; Yokota, T.; Saito, T.; Okazawa, H.; Nagata, T.; Takeda, S.I. In-frame Dystrophin Following Exon 51-Skip** Improves Muscle Pathology and Function in the Exon 52–Deficient mdx Mouse. Mol. Ther. 2010, 18, 1995–2005. [Google Scholar] [CrossRef]
- Aartsma-Rus, A.; Krieg, A.M. FDA Approves Eteplirsen for Duchenne Muscular Dystrophy: The Next Chapter in the Eteplirsen Saga. Nucleic Acid Ther. 2017, 27, 1–3. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mendell, J.R.; Goemans, N.; Lowes, L.P.; Alfano, L.N.; Berry, K.; Shao, J.; Kaye, E.M.; Mercuri, E. Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy. Ann. Neurol. 2016, 79, 257–271. [Google Scholar] [CrossRef] [PubMed]
- Heo, Y.-A. Golodirsen: First Approval. Drugs 2020, 80, 329–333. [Google Scholar] [CrossRef] [PubMed]
- Frank, D.E.; Schnell, F.J.; Akana, C.; El-Husayni, S.H.; Desjardins, C.A.; Morgan, J.; Charleston, J.S.; Sardone, V.; Domingos, J.; Dickson, G.; et al. Increased dystrophin production with golodirsen in patients with Duchenne muscular dystrophy. Neurology 2020, 94, e2270–e2282. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Aartsma-Rus, A.; Corey, D.R. The 10th Oligonucleotide Therapy Approved: Golodirsen for Duchenne Muscular Dystrophy. Nucleic Acid Ther. 2020, 30, 67–70. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Roshmi, R.R.; Yokota, T. Viltolarsen for the treatment of Duchenne muscular dystrophy. Drugs Today 2019, 55, 627–639. [Google Scholar] [CrossRef] [PubMed]
- Dhillon, S. Viltolarsen: First Approval. Drugs 2020, 80, 1027–1031. [Google Scholar] [CrossRef]
- McDonald, C.M.; Wong, B.; Flanigan, K.M.; Wilson, R.; de Kimpe, S.; Lourbakos, A.; Lin, Z.; Campion, G.; DEMAND V study group. Placebo-controlled Phase 2 Trial of Drisapersen for Duchenne Muscular Dystrophy. Ann. Clin. Transl. Neurol. 2018, 5, 913–926. [Google Scholar] [CrossRef] [Green Version]
- Bosgra, S.; Sipkens, J.; de Kimpe, S.; den Besten, C.; Datson, N.; van Deutekom, J. The Pharmacokinetics of 2′-O-Methyl Phosphorothioate Antisense Oligonucleotides: Experiences from Develo** Exon Skip** Therapies for Duchenne Muscular Dystrophy. Nucleic Acid Ther. 2019, 29, 305–322. [Google Scholar] [CrossRef]
- Amantana, A.; Moulton, H.M.; Cate, M.L.; Reddy, M.T.; Whitehead, T.; Hassinger, J.N.; Youngblood, D.S.; Iversen, P.L. Pharmacokinetics, Biodistribution, Stability and Toxicity of a Cell-Penetrating Peptide−Morpholino Oligomer Conjugate. Bioconjug. Chem. 2007, 18, 1325–1331. [Google Scholar] [CrossRef]
- Gait, M.J.; Arzumanov, A.A.; McClorey, G.; Godfrey, C.; Betts, C.; Hammond, S.; Wood, M.J.A. Cell-Penetrating Peptide Conjugates of Steric Blocking Oligonucleotides as Therapeutics for Neuromuscular Diseases from a Historical Perspective to Current Prospects of Treatment. Nucleic Acid Ther. 2018, 29, 1–12. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tsoumpra, M.K.; Fukumoto, S.; Matsumoto, T.; Takeda, S.; Wood, M.J.A.; Aoki, Y. Peptide-conjugate antisense based splice-correction for Duchenne muscular dystrophy and other neuromuscular diseases. EBioMedicine 2019, 45, 630–645. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zaw, K.; Greer, K.; Aung-Htut, M.T.; Mitrpant, C.; Veedu, R.N.; Fletcher, S.; Wilton, S.D. Consequences of Making the Inactive Active Through Changes in Antisense Oligonucleotide Chemistries. Front. Genet. 2019, 10, 1249. [Google Scholar] [CrossRef] [PubMed]
- Lin, C.; Han, G.; Ning, H.; Song, J.; Ran, N.; Yi, X.; Seow, Y.; Yin, H. Glycine Enhances Satellite Cell Proliferation, Cell Transplantation, and Oligonucleotide Efficacy in Dystrophic Muscle. Mol. Ther. 2020, 28, 1339–1358. [Google Scholar] [CrossRef]
- Lu, Q.L.; Rabinowitz, A.; Chen, Y.C.; Yokota, T.; Yin, H.; Alter, J.; Jadoon, A.; Bou-Gharios, G.; Partridge, T. Systemic delivery of antisense oligoribonucleotide restores dystrophin expression in body-wide skeletal muscles. Proc. Natl. Acad. Sci. USA 2005, 102, 198–203. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Nguyen, Q.; Yokota, T. Antisense oligonucleotides for the treatment of cardiomyopathy in Duchenne muscular dystrophy. Am. J. Transl. Res. 2019, 11, 1202–1218. [Google Scholar]
- Yin, H.; Moulton, H.M.; Seow, Y.; Boyd, C.; Boutilier, J.; Iverson, P.; Wood, M.J.A. Cell-penetrating peptide-conjugated antisense oligonucleotides restore systemic muscle and cardiac dystrophin expression and function. Hum. Mol. Genet. 2008, 17, 3909–3918. [Google Scholar] [CrossRef] [Green Version]
- Li, Q.; Xu, M.; Cui, Y.; Huang, C.; Sun, M. Arginine-rich membrane-permeable peptides are seriously toxic. Pharmacol. Res. Perspect. 2017, 5. [Google Scholar] [CrossRef]
- Duan, D. Systemic AAV Micro-dystrophin Gene Therapy for Duchenne Muscular Dystrophy. Mol. Ther. 2018, 26, 2337–2356. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tedesco, F.S. Human artificial chromosomes for Duchenne muscular dystrophy and beyond: Challenges and hopes. Chromosome Res. 2015, 23, 135–141. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Harper, S.Q.; Hauser, M.A.; DelloRusso, C.; Duan, D.; Crawford, R.W.; Phelps, S.F.; Harper, H.A.; Robinson, A.S.; Engelhardt, J.F.; Brooks, S.V.; et al. Modular flexibility of dystrophin: Implications for gene therapy of Duchenne muscular dystrophy. Nat. Med. 2002, 8, 253–261. [Google Scholar] [CrossRef] [PubMed]
- Hermonat, P.L.; Muzyczka, N. Use of adeno-associated virus as a mammalian DNA cloning vector: Transduction of neomycin resistance into mammalian tissue culture cells. Proc. Natl. Acad. Sci. USA 1984, 81, 6466–6470. [Google Scholar] [CrossRef] [Green Version]
- Le Guiner, C.; Servais, L.; Montus, M.; Larcher, T.; Fraysse, B.; Moullec, S.; Allais, M.; François, V.; Dutilleul, M.; Malerba, A.; et al. Long-term microdystrophin gene therapy is effective in a canine model of Duchenne muscular dystrophy. Nat. Commun. 2017, 8, 16105. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- England, S.B.; Nicholson, L.V.; Johnson, M.A.; Forrest, S.M.; Love, D.R.; Zubrzycka-Gaarn, E.E.; Bulman, D.E.; Harris, J.B.; Davies, K.E. Very mild muscular dystrophy associated with the deletion of 46% of dystrophin. Nature 1990, 343, 180–182. [Google Scholar] [CrossRef] [PubMed]
- Koo, T.; Popplewell, L.; Athanasopoulos, T.; Dickson, G. Triple trans-splicing adeno-associated virus vectors capable of transferring the coding sequence for full-length dystrophin protein into dystrophic mice. Hum. Gene Ther. 2014, 25, 98–108. [Google Scholar] [CrossRef] [PubMed]
- Kornegay, J.N.; Li, J.; Bogan, J.R.; Bogan, D.J.; Chen, C.; Zheng, H.; Wang, B.; Qiao, C.; Howard, J.F.; ** in Duchenne patients. Mol. Ther. J. Am. Soc. Gene Ther. 2014, 22, 1923–1935. [Google Scholar] [CrossRef] [Green Version]
- Gentil, C.; Le Guiner, C.; Falcone, S.; Hogrel, J.-Y.; Peccate, C.; Lorain, S.; Benkhelifa-Ziyyat, S.; Guigand, L.; Montus, M.; Servais, L.; et al. Dystrophin Threshold Level Necessary for Normalization of Neuronal Nitric Oxide Synthase, Inducible Nitric Oxide Synthase, and Ryanodine Receptor-Calcium Release Channel Type 1 Nitrosylation in Golden Retriever Muscular Dystrophy Dystrophinopathy. Hum. Gene Ther. 2016, 27, 712–726. [Google Scholar] [CrossRef]
- Neri, M.; Torelli, S.; Brown, S.; Ugo, I.; Sabatelli, P.; Merlini, L.; Spitali, P.; Rimessi, P.; Gualandi, F.; Sewry, C.; et al. Dystrophin levels as low as 30% are sufficient to avoid muscular dystrophy in the human. Neuromuscul. Disord. NMD 2007, 17, 913–918. [Google Scholar] [CrossRef]
- Beekman, C.; Janson, A.A.; Baghat, A.; van Deutekom, J.C.; Datson, N.A. Use of capillary Western immunoassay (Wes) for quantification of dystrophin levels in skeletal muscle of healthy controls and individuals with Becker and Duchenne muscular dystrophy. PLoS ONE 2018, 13, e0195850. [Google Scholar] [CrossRef]
- Nicholson, L.V. The “rescue” of dystrophin synthesis in boys with Duchenne muscular dystrophy. Neuromuscul. Disord. NMD 1993, 3, 525–531. [Google Scholar] [CrossRef]
- Waldrop, M.A.; Gumienny, F.; El Husayni, S.; Frank, D.E.; Weiss, R.B.; Flanigan, K.M. Low-level dystrophin expression attenuating the dystrophinopathy phenotype. Neuromuscul. Disord. NMD 2018, 28, 116–121. [Google Scholar] [CrossRef]
- Wells, D.J. What is the level of dystrophin expression required for effective therapy of Duchenne muscular dystrophy? J. Muscle Res. Cell Motil. 2019, 40, 141–150. [Google Scholar] [CrossRef]
- Goldstein, J.M.; Tabebordbar, M.; Zhu, K.; Wang, L.D.; Messemer, K.A.; Peacker, B.; Ashrafi Kakhki, S.; Gonzalez-Celeiro, M.; Shwartz, Y.; Cheng, J.K.W.; et al. In Situ Modification of Tissue Stem and Progenitor Cell Genomes. Cell Rep. 2019, 27, 1254–1264. [Google Scholar] [CrossRef] [Green Version]
- Charville, G.W.; Cheung, T.H.; Yoo, B.; Santos, P.J.; Lee, G.K.; Shrager, J.B.; Rando, T.A. Ex Vivo Expansion and In Vivo Self-Renewal of Human Muscle Stem Cells. Stem Cell Rep. 2015, 5, 621–632. [Google Scholar] [CrossRef] [Green Version]
- Arnett, A.L.; Konieczny, P.; Ramos, J.N.; Hall, J.; Odom, G.; Yablonka-Reuveni, Z.; Chamberlain, J.R.; Chamberlain, J.S. Adeno-associated viral (AAV) vectors do not efficiently target muscle satellite cells. Mol. Ther. Methods Clin. Dev. 2014, 1, 14038. [Google Scholar] [CrossRef]
- Muraine, L.; Bensalah, M.; Dhiab, J.; Cordova, G.; Arandel, L.; Marhic, A.; Chapart, M.; Vasseur, S.; Benkhelifa-Ziyyat, S.; Bigot, A.; et al. Transduction Efficiency of Adeno-Associated Virus Serotypes After Local Injection in Mouse and Human Skeletal Muscle. Hum. Gene Ther. 2020, 31, 233–240. [Google Scholar] [CrossRef]
- Nance, M.E.; Shi, R.; Hakim, C.H.; Wasala, N.B.; Yue, Y.; Pan, X.; Zhang, T.; Robinson, C.A.; Duan, S.X.; Yao, G.; et al. AAV9 Edits Muscle Stem Cells in Normal and Dystrophic Adult Mice. Mol. Ther. 2019, 27, 1568–1585. [Google Scholar] [CrossRef]
Chemical | Drug | Other Name | Sponsor | Targeted Exon | Clinical Trial Number | Trial Phase | Start Date | Completion Date |
---|---|---|---|---|---|---|---|---|
PMO 1 | Eteplirsen | AVI-4658, Exondys 51 | Sarepta Therapeutics | Exon 51 | NCT03218995 | 2 | August 2017 | March 2021 |
NCT04179409 | 2 | February 2020 | September 2022 | |||||
NCT03992430 | 3 | January 2020 | October 2024 | |||||
NCT03985878 | 3 | June 2019 | February 2027 | |||||
Golodirsen | SRP4053 | Sarepta Therapeutics | Exon 53 | NCT04179409 | 2 | February 2020 | September 2022 | |
NCT02500381 | 3 | September 2016 | May 2023 | |||||
NCT03532542 | 3 | 2 August 2018 | 10 August 2026 | |||||
Casimersen | SRP4045 | Sarepta Therapeutics | Exon 45 | NCT04179409 | 2 | February 2020 | September 2022 | |
NCT03532542 | 3 | 2 August 2018 | 10 August 2026 | |||||
Viltolarsen | NCNP-01, NS-065 | Nippon Shinyaku Co Ltd. | Exon 53 | NCT03167255 | 2 | July 2017 | August 2021 | |
NCT04060199 | 3 | April 2020 | December 2024 | |||||
2′-O-methyl PS | Drisapersen | PRO051, GSK2402968 | BioMarin Pharmaceutical Inc. | Exon 51 | NCT02636686 | Extension | December 2015 | January 2018 |
DS-5141b | Daiichi Sankyo Co., Ltd. | Exon 45 | NCT02667483 | 1, 2 | October 2015 | December 2020 | ||
PPMO 2 | SRP-5051 | Sarepta Therapeutics | Exon 51 | NCT03675126 | 1, 2 | December 2018 | July 2024 | |
NCT04004065 | 2 | June 2019 | August 2021 | |||||
Stereopure | Suvodirsen | WVE-210201 | Wave Life Sciences Ltd. | Exon 51 | NCT03907072 | 2, 3 | September 2019 | January 2020 |
Sponsor | Nationwide Children’s Hospital | Solid Biosciences, LLC | Sarepta Therapeutics, Inc. | Pfizer | Kevin Flanigan | Jerry R. Mendell |
---|---|---|---|---|---|---|
ClinicalTrials.gov Identifier | NCT00428935 | NCT03368742 | NCT03375164 | NCT03362502 | NCT03333590 | NCT02376816 |
Trial Title | Safety study of minidystrophin gene to treat Duchenne Muscular Dystrophy | Microdystrophin gene transfer study in adolescents and children with DMD (IGNITE DMD) | Systemic gene delivery clinical trial for Duchenne Muscular Dystrophy | A study to evaluate the safety and tolerability of PF-06939926 gene therapy in Duchenne Muscular Dystrophy | Gene transfer clinical trial to deliver rAAVrh74.MCK.GALGT2 for Duchenne Muscular Dystrophy | Clinical intramuscular gene transfer trial of rAAVrh74.MCK. microdystrophin to patients With Duchenne Muscular Dystrophy |
Recruitment Status | Completed | Suspended (clinical hold) | Active, not recruiting | Recruiting | Active, not recruiting | Completed |
Study Start Date | March 2006 | 6 December 2017 | 4 January 2018 | 23 January 2018 | 6 November 2017 | March 2015 |
(Estimated) Study Completion Date | July 2010 | March 2021 | April 2021 | 26 August 2025 | November 2021 | September 2017 |
Intervention/Treatment | Biological: rAAV2.5-CMV-minidystrophin (d3990) | Genetic: SGT-001 | Genetic: rAAVrh74.MHCK7 microdystrophin | Genetic: PF-06939926 | Biological: rAAVrh74.MCK.GALGT2 | Biological: rAAVrh74.MCK. microdystrophin |
Enrollment | 6 participants | 16 participants | 4 participants | 15 participants | 6 participants | 2 participants |
Patient Age | 5–12 years | 4–17 years | 3 months to 7 years | 4–12 years | 4 years and older | 7 years and older |
Dose | Cohort 1: 2.0E10 vg/kg Cohort 2: 1.0E11 vg/kg | Ascending doses (quantitative value not reminded) | 2.0E14 vg/kg in 10 mL/kg | Ascending doses (quantitative value not reminded) | Cohort 1: 5.0E13 vg/kg Cohort 2: 1.0E14 vg/kg | Cohort 1: 3E11 vg/single foot Cohort 2: 1E12 vg/single foot |
AAV Serotype | AAV2.5 | AAV9 | AAVrh74 | AAV9 | AAVrh74 | AAVrh74 |
Delivery Type | Intramuscular injection into biceps muscle | Intravenous injection | Intravenous injection into peripheral arm vein | Intravenous injection | Intravascular limb infusion | Intramuscular injection into Extensor digitorum brevis (EDB) muscle |
Primary Outcome | Safety and tolerability [88] | Safety | Safety | Safety and tolerability | Safety | Safety |
Secondary Outcome | Minidystrophin gene expression and muscle strength test [88] | No secondary outcome yet | Microdystrophin expression and muscle motility assessment | Minidystrophin gene expression, muscle strength and quality | GALGT2 gene expression and muscle motility assessment | Transgene expression |
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Sun, C.; Shen, L.; Zhang, Z.; **e, X. Therapeutic Strategies for Duchenne Muscular Dystrophy: An Update. Genes 2020, 11, 837. https://doi.org/10.3390/genes11080837
Sun C, Shen L, Zhang Z, **e X. Therapeutic Strategies for Duchenne Muscular Dystrophy: An Update. Genes. 2020; 11(8):837. https://doi.org/10.3390/genes11080837
Chicago/Turabian StyleSun, Chengmei, Luoan Shen, Zheng Zhang, and **n **e. 2020. "Therapeutic Strategies for Duchenne Muscular Dystrophy: An Update" Genes 11, no. 8: 837. https://doi.org/10.3390/genes11080837