Several unexpected fatalities in patients who received adeno-associated virus (AAV)-based gene therapies have recently occurred. These tragic events have cast a pall over the entire sector with some stakeholders suggesting that AAV is patently unsafe as a gene delivery platform and ought not to be pursued. This conclusion is not warranted.
DobrzynskiE, MingozziF, LiuYL, et al.Induction of antigen-specific CD4+ T-cell anergy and deletion by in vivo viral gene transfer. Blood, 2004; 104(4):969–977; doi: 10.1182/blood-2004-03-0847
MingozziF, LiuYL, DobrzynskiE, et al.Induction of immune tolerance to coagulation factor IX antigen by in vivo hepatic gene transfer. J Clin Invest, 2003; 111(9):1347–1356; doi: 10.1172/jci16887
7.
RaperSE, ChirmuleN, LeeFS, et al.Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. Mol Genet Metab, 2003; 80(1–2):148–158; doi: 10.1016/j.ymgme.2003.08.016
8.
FeldmanAG, ParsonsJA, DutmerCM, et al.Subacute liver failure following gene replacement therapy for spinal muscular atrophy type 1. J Pediatr, 2020; 225:252–258.e1; doi: 10.1016/j.jpeds.2020.05.044
9.
ShiehPB, KuntzNL, DowlingJJ, et al.Safety and efficacy of gene replacement therapy for X-linked myotubular myopathy (ASPIRO): A multinational, open-label, dose-escalation trial. Lancet Neurol, 2023; 22(12):1125–1139; doi: 10.1016/s1474-4422(23)00313-7
10.
ChandDH, ZaidmanC, AryaK, et al.Thrombotic microangiopathy following onasemnogene abeparvovec for spinal muscular atrophy: A case series. J Pediatr, 2021; 231:265–268; doi: 10.1016/j.jpeds.2020.11.054
LekA, WongB, KeelerA, et al.Death after high-dose rAAV9 gene therapy in a patient with Duchenne’s muscular dystrophy. N Engl J Med, 2023; 389(13):1203–1210; doi: 10.1056/NEJMoa2307798
HordeauxJ, LamontagneRJ, BandyopadhyayS, et al.Lung endothelial transduction in a patient that succumbed to acute respiratory distress syndrome following high-dose rAAV9 gene therapy. Mol Ther, 2025; 33(6):2339–2342; doi: 10.1016/j.ymthe.2025.05.017
15.
GreenbergB, TaylorM, AdlerE, et al.Phase 1 study of AAV9.LAMP2B gene therapy in Danon disease. N Engl J Med, 2025; 392(10):972–983; doi: 10.1056/NEJMoa2412392
16.
SalabarriaSM, CortiM, ColemanKE, et al.Thrombotic microangiopathy following systemic AAV administration is dependent on anti-capsid antibodies. J Clin Invest, 2024; 134(1):e173510; doi: 10.1172/jci173510
