Strategies for Bottlenecks of rAAV-Mediated Expression in Skeletal and Cardiac Muscle of Duchenne Muscular Dystrophy
Abstract
:1. Introduction
2. Current Situation of DMD Treatment
3. Clinical Development of Systemic AAV-Mediated Mini/Micro-Dystrophin Gene Therapy
3.1. Sarepta-SRP-9001
3.2. Pfizer-PF-06939926
3.3. Solid Biosciences-SGT-001
4. Possible Bottlenecks of Clinical Trials of rAAV- Mediated Gene Therapies for DMD
4.1. Immune Response to High-Dose Systemic AAV May Account for Acute Toxicity
4.2. The Mini/Micro-Dystrophin Was Recognized as “Nonconformist” and Destroyed by Overactive Immune Cells, Reducing the Therapeutic Effect
4.3. Fibrosis of Skeletal Muscle Cells and Myocardial Cells Directly Affects the Therapeutic Microenvironment
5. Several Strategies Are Currently under Development to Overcome the Bottlenecks
5.1. MyoAAV, Which Targets Striated Muscle Transduction, Presents Great Therapeutic Potential for DMD after Injection of a Low Dose of Virus
5.2. Expression Cassette Structure Optimization
5.2.1. Utrophin as the Expression Cassette to Circumvent the Potential Immune Response of Dystrophin
5.2.2. Small Activation RNA Targeting the Promoter Region of Mini/Micro-Utrophin Can Be Used to Improve the Transcription Level of Mini/Micro-Utrophin
5.2.3. The 5′UTR Region Was Optimized to Enhance the Translation Level of Mini/Micro-Utrophin
5.3. CDCs Therapy Modulates Immune Response and Anti-Fibrosis, Providing an Effective Therapeutic Microenvironment for Gene Therapy of DMD
5.4. Immune Suppression May Be the Promising Approach to Manage Capsid or, Potentially, Transgene Immunogenicity
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Sarepta | Pfizer | Therapeutics Solid Biosciences | |
---|---|---|---|
Trial name | An open-label, systemic gene delivery study using commercial process material to evaluate the safety of and expression from SRP-9001 in subjects with Duchenne muscular dystrophy (ENDEAVOR) | A phase 1b multicenter, open-label, single ascending dose study to evaluate the safety and tolerability of pf-06939926 in ambulatory and non-ambulatory subjects with Duchenne muscular dystrophy | A randomized, controlled, open-label, single-ascending dose, phase I/II study to investigate the safety and tolerability, and efficacy of intravenous SGT-001 in male adolescents and children with Duchenne muscular dystrophy |
ClinicalTrials.gov Identififier | NCT04626674 | NCT03362502 | NCT03368742 |
Study nature | Phase-1b trial | Phase 1b, open-label, trial | Phase 1/2, open-label, trial |
Drug name | SRP-9001 | PF-06939926 | SGT-001 |
AAV-serotype | rAAV-rh74 | rAAV9 | rAAV9 |
Dose | 1 dose (1.33 × 1014 vg/kg) for cohort 1 | 2 doses (1.0 × 1014 vg/kg, 3.0 × 1014 vg/kg) | 2 doses (5.0 × 1013 vg/kg 2.0 × 1014 vg/kg) |
Patient number | 38 | 22 | 16 (estimated enrollment) |
Patient average age | 3 years and older | 4 years and older | 4~17 years |
Disease stage | Ambulatory and non-ambulatory subjects | Ambulatory and non-ambulatory subjects | Ambulatory and non-ambulatory subjects |
Corticosteroid use | 3 months on stable weekly dose of oral corticosteroids for cohort 1 | Daily glucocorticoids for at least 3 months | Stable daily dose (or equivalent) of oral corticosteroids ≥ 12 wks |
Dystrophin gene mutation | Any mutation | Any mutation | Any mutation |
Pre-Nab to AAV | Negative | Negative | Negative |
Primary outcome | The change in micro-dystrophin expression in DMD patients treated with SRP-9001. | Safety and tolerability | Safety |
Secondary outcome | Adverse events, vector shedding, and the development of antibodies to AAVrh74. | Micro-dystrophin expression in biopsy | |
SAE | Increased transaminases that required corticosteroid treatment. Nausea and vomiting that required intravenous treatment (cohort 1). | More than 40% of patients suffered vomiting, nausea, decreased appetite, and pyrexia. | Complement activation, reduced platelet count, liver dysfunction, and acute kidney injury |
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Li, N.; Song, Y. Strategies for Bottlenecks of rAAV-Mediated Expression in Skeletal and Cardiac Muscle of Duchenne Muscular Dystrophy. Genes 2022, 13, 2021. https://doi.org/10.3390/genes13112021
Li N, Song Y. Strategies for Bottlenecks of rAAV-Mediated Expression in Skeletal and Cardiac Muscle of Duchenne Muscular Dystrophy. Genes. 2022; 13(11):2021. https://doi.org/10.3390/genes13112021
Chicago/Turabian StyleLi, Na, and Yafeng Song. 2022. "Strategies for Bottlenecks of rAAV-Mediated Expression in Skeletal and Cardiac Muscle of Duchenne Muscular Dystrophy" Genes 13, no. 11: 2021. https://doi.org/10.3390/genes13112021
APA StyleLi, N., & Song, Y. (2022). Strategies for Bottlenecks of rAAV-Mediated Expression in Skeletal and Cardiac Muscle of Duchenne Muscular Dystrophy. Genes, 13(11), 2021. https://doi.org/10.3390/genes13112021