Unexpected Death of a Duchenne Muscular Dystrophy Patient in an N-of-1 Trial of rAAV9-delivered CRISPR-transactivator
Lek, A.; Wong, B.; Keeler, A.; Blackwood, M.; Ma, K.; Huang, S.; Sylvia, K.; Batista, A. R.; Artinian, R.; Kokoski, D.; Parajuli, S.; Putra, J.; Carreon, C. K.; Lidov, H.; Woodman, K.; Pajusalu, S.; Spinazzola, J.; Gallagher, T.; LaRovere, J.; Baulderson, D.; Black, L.; Sutton, K.; Horgan, R.; Lek, M.; Flotte, T.
Show abstract
An N-of-1 trial was developed to deliver a dCas9-VP64 transgene designed to upregulate the cortical dystrophin as a custom therapy for a Duchenne muscular dystrophy (DMD) patient. After showing signs of mild cardiac dysfunction and pericardial effusion, the patient acutely decompensated and sustained cardiac arrest six-days after dosing and succumbed two-days later. Post-mortem examination revealed severe acute-respiratory distress syndrome with diffuse alveolar damage. Vector biodistribution data was obtained and revealed minimal expression of transgene in liver. There was no evidence of AAV9 antibodies nor of effector T cell reactivity. These findings demonstrate innate immune signaling with capillary leak as a form of toxicity in an advanced DMD case treated with high-dose rAAV gene therapy.
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