CRISPR-mediated exon skipping or base editing for DMD c.1950T>A (p.Cys650Ter): restoring the dystrophin reading frame in exon 15

For DMD c.1950T>A (p.Cys650Ter), a nonsense variant in exon 15 of the dystrophin gene, CRISPR-mediated strategies offer two complementary approaches: (1) permanent exon skipping via disruption of the exon 15 splice acceptor or donor to exclude the nonsense-containing exon from mature mRNA, producing an internally truncated but partially functional Becker-like dystrophin, or (2) direct base editing to revert the stop codon if the target adenine falls within an ABE editing window. Both approaches aim to restore dystrophin expression in skeletal and cardiac muscle. CRISPR-based permanent exon skipping has the advantage over ASO-based exon skipping (e.g., eteplirsen-class drugs) of requiring only a single treatment to achieve lifelong reading frame restoration, versus chronic weekly/monthly ASO injections.

CRISPR-mediated exon skipping has been demonstrated in DMD patient-derived iPSC-cardiomyocytes and in deltaE50-mdx mice, where Cas9-mediated disruption of exon splice sites restores dystrophin expression and improves muscle function (Amoasii et al., Science 2018; PMID:29439201). In vivo AAV-CRISPR delivery to skeletal and cardiac muscle has shown sustained dystrophin restoration over 12+ months in canine DMD models (Amoasii et al., Nat Med 2018; PMID:30250058). For p.Cys650Ter in exon 15, exon skipping of exon 15 (or exons 14-15 to maintain reading frame depending on phase) would remove 81-162 amino acids from the spectrin-repeat rod domain — a region tolerant of internal deletions based on Becker muscular dystrophy genotype-phenotype correlations. ClinVar classifies this variant as Pathogenic. Alternatively, ABE could potentially convert the TAA stop codon (from the c.1950T>A change creating a TGA→TAA stop on the sense strand; the antisense target A could be edited to G) to restore a sense codon. Vertex/CRISPR Therapeutics and Editas Medicine are advancing in vivo CRISPR-DMD programs, though none have reached Phase 3.

No in vivo CRISPR gene editing therapy for DMD has been approved or completed Phase 3 trials as of early 2026. AAV-mediated delivery of CRISPR components to sufficient skeletal muscle mass (30-40% of body weight) requires high systemic AAV doses with associated hepatotoxicity and immune response risks. Pre-existing anti-Cas9 immunity (present in ~65% of humans for SpCas9) may limit editing efficiency. Cardiac muscle transduction is critical for long-term survival but may require separate dosing optimization. For p.Cys650Ter specifically, the exon skipping strategy depends on exon 15 removal maintaining the reading frame — this requires confirmation that the exon 14-exon 16 junction produces an in-frame transcript. Off-target editing in the large dystrophin gene (2.4 Mb) and elsewhere in the genome requires thorough safety characterization. The Becker-like truncated dystrophin produced by exon skipping provides partial function but is not equivalent to full-length dystrophin — the degree of clinical benefit depends on which spectrin repeats are deleted and whether the nNOS-binding domain is preserved. Long-term durability of editing in post-mitotic myonuclei is expected to be stable, but editing in proliferating satellite cells is needed for regeneration-dependent muscle maintenance.