Deaths in gene therapy of Duchenne muscular dystrophy and other diseases: Underlying mechanisms and mitigating strategies

Duchenne muscular dystrophy (DMD) is a fatal muscle degenerating disease caused by dystrophin deficiency. Adeno-associated virus (AAV)-based gene therapy holds promise for restoring missing dystrophin and improving quality of life. Many clinical trials have been conducted or are ongoing. Despite compelling preclinical data, the full potential of AAV gene therapy remains to be established in DMD patients. Importantly, high-dose intravenous AAV administration has resulted in hospitalizations and several deaths in patients afflicted by DMD and other inherited diseases due to innate and adaptive immune responses to the vectors. Although fatal outcomes are rare, a critical analysis of these cases may provide insights to refine systemic AAV gene therapy for DMD and other inherited diseases. Here, we review the clinical findings of the reported deaths and related cases in AAV gene therapy for DMD and other diseases. We also evaluate the underlying mechanisms and discuss mitigating strategies and future directions.