Death following high-dose AAV9 gene therapy in a patient with advanced SMA-PME.

Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) is an ultra-rare, fatal autosomal-recessive disorder caused by ASAH1 mutations, with no curative treatment. We report the first-in-human intravenous administration of an AAV9 vector carrying the human ASAH1 coding sequence in a 15-year-old female with advanced SMA-PME (heterozygous ASAH1 c.456A>C and c.918-2A>G mutations). The patient presented with severe neuromuscular impairment, deafness, and recurrent myoclonic status epilepticus, without detectable anti-AAV9 neutralizing antibodies. A marked clinical deterioration warranted compassionate use (GNT-017-ASAH-CU). A dose of 2.2 × 1014 vector genomes per kilogram of body weight was administered under prophylactic prednisolone and sirolimus. The patient experienced rapid onset of complement activation leading to cytokine-mediated capillary leak syndrome, culminating in refractory shock, multiorgan failure, and death on day 8. A postmortem examination revealed acute circulatory failure as the cause of death without myocarditis or thrombotic microangiopathy. Some endothelial injury was suggested by a rise in von Willebrand factor from days 4 to 8, paralleled by increased hyaluronic acid on days 7 and 8. These findings underscore the potential for life-threatening innate immune activation in patients with advanced SMA-PME receiving high-dose systemic AAV9 gene therapy, highlighting the need to identify high-risk patients and proactively monitor biomarkers of endothelial injury.