Dystrophin gene (DMD) locus, proximal exons 1–19 region (DMD)

The DMD gene locus, specifically the proximal exons 1–19 region, serves as a critical genomic target for gene-editing therapies aimed at treating Duchenne Muscular Dystrophy (DMD). The DMD gene is the largest in the human genome and encodes dystrophin, a protein vital for maintaining the structural integrity of muscle cell membranes by linking the internal cytoskeleton to the extracellular matrix (UniProt: P11532). Mutations in this region often disrupt the open reading frame, leading to a complete absence of functional dystrophin and subsequent progressive muscle degeneration (PubMed: 26720508). Engineered SpCas9/sgRNA systems are designed to target specific sequences within these exons to induce double-strand breaks, facilitating the restoration of the reading frame through exon skipping or deletion (PubMed: 30283143). This therapeutic approach seeks to convert a severe DMD phenotype into a milder Becker Muscular Dystrophy (BMD) phenotype by enabling the expression of a partially functional dystrophin protein. Clinical development focuses on optimizing delivery via adeno-associated viruses (AAV) and minimizing off-target effects to ensure safety and efficacy in pediatric populations. Successful editing at this locus is monitored through the restoration of dystrophin expression in muscle biopsies and improvements in motor function.

Other names

DMD geneDystrophin locusDMD exons 1-19DMD proximal exon regionDMD genomic target site

The mechanism of action involves the use of an engineered CRISPR-Cas9 system, specifically Streptococcus pyogenes Cas9 (SpCas9) and a single guide RNA (sgRNA), to target the proximal exons 1-19 of the DMD gene. The sgRNA directs the Cas9 nuclease to a specific genomic sequence, where it induces a double-strand break (DSB). This break is typically repaired by the cell's non-homologous end joining (NHEJ) pathway, leading to targeted deletions or insertions that can restore the reading frame of the dystrophin gene, thereby allowing for the production of a truncated but functional dystrophin protein (PubMed: 26720508, PubMed: 30283143).