P4.015: Analysis of the effectiveness of CRISPR and gene therapy in Duchenne Muscular Dystrophy

Background: Duchenne muscular dystrophy (DMD) is a neuromuscular disease caused by a mutation in the DMD gene, leading to progressive muscle degeneration and early death. It affects approximately 1 in 3,500 to 1 in 5,000 live male births, with a prevalence of around 7.1 cases per 100,000 males. Current treatments focus on symptom management rather than a cure. CRISPR/Cas9 gene editing holds promise for restoring dystrophin function and improving clinical outcomes, though challenges remain in delivery and immunogenicity.Based on clinical trial results, this study aims to evaluate the efficacy of CRISPR/Cas9 gene editing in restoring dystrophin function in DMD patients.

Methods: Data from recent clinical trials using CRISPR/Cas9 for DMD were analyzed, focusing on dystrophin restoration percentages, functional improvements, and adverse effects. Studies included AAV-mediated micro-dystrophin delivery trials, CRISPR-based exon skipping strategies, and Base editing approaches.

Results: The large size of the dystrophin gene poses limitations for this mode of treatment, but the target can potentially be the smaller microdystrophins.
Despite these advancements, adeno-associated viral (AAV) vector delivery needs refinement to optimize efficiency and minimize immune responses. The major immune response seen in patients was due to the innate immunity response following high-dose rAAV gene therapy, which led to acute respiratory distress syndrome (ARDS) and mild cardiac distress.

Conclusion: DMD is a genetic disorder that results in progressive muscle degeneration and early death of individuals with it. It is known to be caused by mutations in the gene encoding protein-dystrophin. CRISPR/Cas9 gene editing represents a groundbreaking approach to treating DMD, with dystrophin restoration reaching up to 50% in early trials. Although the AAV vector has proven widely effective in preclinical models and early clinical trials, its limitation involves a 30% immune response affecting the lungs and heart, leading to ARDS. However, challenges related to immune responses, delivery methods, and long-term effects must be addressed before widespread clinical implementation. Future studies should optimize delivery mechanisms, refine gene-editing precision, and develop immunomodulatory strategies. Other therapies that have the potential to skim the dystrophin gene are Exon skipping and stop codon readthrough. Continued advancements in genetic therapies can revolutionize DMD care, offering hope for a more effective and lasting treatment for affected individuals.