Considering New Duchenne Muscular Dystrophy Therapies: Exon Skipping and Gene Therapy

Clinical Brief: Genetic Therapy Eligibility in Advanced DMD

Main Discussion Topics

• Expansion of gene therapy eligibility criteria to include older, non-ambulatory patients
• Potential exclusion criteria for gene therapy, particularly mutations in exons 8-9
• Immunological considerations including pre-existing AAV antibodies
• Limited data on efficacy in older patients with advanced disease

Key Points for Physicians

• Accurate genetic diagnosis is essential for determining therapeutic eligibility
• Mutations in exon 8-9 region may increase risk of immune response to microdystrophin (~10-15% of patients)
• Pre-existing AAV antibodies (seropositivity) preclude gene therapy eligibility
• Recent expansion of approval allows treatment consideration even for 16-year-old patients

Notable Insights

The expert notes evolving exclusion criteria with initial exclusion of exons 1-19 mutations now narrowing to primarily exons 8-9, but cautions that other immunogenic regions may be identified as more patients are treated. Lack of published data on older patient outcomes represents a significant knowledge gap.

Clinical Significance

Despite expanded eligibility criteria for genetic therapies, careful patient selection remains critical, with mutation-specific considerations and immunological status determining appropriate candidates even in advanced disease stages.