Is duchenne gene therapy a suitable treatment despite its immunogenic class effect?

Introduction: Duchenne muscular dystrophy (DMD) is a severe X-linked disorder characterized by progressive muscle weakness and eventual death due to cardiomyopathy or respiratory complications. Currently, there is no cure for DMD, with standard treatments primarily focusing on symptom management. Using immunosuppressive measures and optimized vector designs allow for gene therapies to better address the underlying genetic cause of the disease.

Areas covered: This review evaluates the efficacy and safety of emerging gene therapies for DMD as of August 2024, particularly focusing on micro-dystrophin/mini-dystrophin therapies and CRISPR-Cas9 gene editing. It also discusses the potential of utrophin upregulation as a therapeutic strategy. It highlights safety concerns associated with these therapies, including adverse events and patient deaths. A comprehensive overview of developments cover topics such as CRISPR-Cas9 therapies, micro-dystrophin, and the potential delivery of full-length dystrophin.

Expert opinion: The FDA's recent approval of delandistrogene moxeparvovec (Elevidys) underscores the promise of gene replacement therapies for dystrophin restoration in DMD patients. Understanding the mechanisms behind the adverse effects and excluding patients with specific pathogenic variants may enhance the safety profiles of these therapies. CRISPR/Cas9 therapies, while promising, face significant regulatory and safety challenges that hinder their clinical application. Optimal DMD therapies should target both skeletal and cardiac muscles to be truly effective.