Genetic strategies for therapy of Duchenne muscular dystrophy
Agnieszka Łoboda, Jeffrey S. Chamberlain, Józef Dulak
Abstract
gene, which encodes dystrophin, an essential structural muscle protein. Currently, there are no cures for DMD, and available therapies primarily focus on alleviating symptoms rather than correcting the underlying genetic defect. However, restoration of a shortened version of dystrophin offers the potential for partially addressing the underlying cause of the disease. This review focuses on the promises and challenges of various genetic strategies, such as exon skipping, gene replacement, and gene editing (e.g., by CRISPR-Cas9) aimed at restoring or replacing the dystrophin expression or upregulating utrophin, a paralog of dystrophin that is primarily expressed during fetal life. Finally, novel approaches for modulatory therapies are considered. While they cannot address the cause of DMD, they offer the potential to attenuate the wide-ranging consequences of dystrophin deficiency. Although some of these interventions have demonstrated encouraging preclinical results and early-stage clinical success, challenges remain in optimizing delivery methods, addressing immune responses, and ensuring long-term therapeutic efficacy. Achieving the latter will be crucial for demonstrating the effectiveness of already registered exon-skipping strategies and gene therapy with microdystrophin, which is of utmost importance for the validity of the field.