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Complement-mediated thrombotic microangiopathy (TMA) in the form of atypical hemolytic uremic syndrome (aHUS) has emerged as an immune complication of systemic adeno-associated virus (AAV) gene transfer that was unforeseen based on nonclinical studies. Understanding this phenomenon in the clinical setting has been limited by incomplete data and a lack of uniform diagnostic and reporting criteria. While apparently rare based on available information, AAV-associated TMA/aHUS can pose a substantial risk to patients including one published fatality. Reported cases were originally limited to pediatric Duchenne muscular dystrophy patients receiving micro- or mini-dystrophin transgenes via AAV9 but have subsequently been reported in both pediatric and adult patients across a range of disorders, transgenes, promoters, and AAV capsid types. This article provides an introduction to the complement system, TMA and aHUS, and anticomplement therapies, then presents clinical reviews of AAV-associated TMA/aHUS cases that have been reported publicly. Finally, exploration of risk factors and current and future mitigation approaches are discussed.
Genevieve Laforet (Thu,) studied this question.