Death after High-Dose rAAV9 Gene Therapy in a Patient with Duchenne’s Muscular Dystrophy
Open accessAbstract
We treated a 27-year-old patient with Duchenne’s muscular dystrophy (DMD) with recombinant adeno-associated virus (rAAV) serotype 9 containing dSaCas9 (i.e., “dead” Staphylococcus aureus Cas9, in which the Cas9 nuclease activity has been inactivated) fused to VP64; this transgene was designed to up-regulate cortical dystrophin as a custom CRISPR–transactivator therapy. The dose of rAAV used was 1×1014 vector genomes per kilogram of body weight. Mild cardiac dysfunction and pericardial effusion developed, followed by acute respiratory distress syndrome (ARDS) and cardiac arrest 6 days after transgene treatment; the patient died 2 days later. A postmortem examination showed severe diffuse alveolar damage. Expression of transgene in the liver was minimal, and there was no evidence of AAV serotype 9 antibodies or effector T-cell reactivity in the organs. These findings indicate that an innate immune reaction caused ARDS in a patient with advanced DMD treated with high-dose rAAV gene therapy. (Funded by Cure Rare Disease.)
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Although AAV is substantially less inflammatory than many other viral vectors, treatments may require high vector doses up to 10^14 vg/kg, particularly for systemic administration.
“Although AAV is substantially less inflammatory compared with many other viral vectors, treatments may require administration of high vector doses of up to 10 14 vg/ kg, in particular for applications that depend on systemic vector administration.”
From Innate immune sensing of adeno-associated virus vectors (2024) · cites this paper as [9]
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- Authors
- 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. M., Gallagher, T., LaRovere, J., Balderson, D., Black, L., Sutton, K., Horgan, R., Lek, M., & Flotte, T.
- Affiliations
- Yale University (US)
- University of Massachusetts Chan Medical School (US)
- Boston Children's Hospital (US)
- Tartu University Hospital (EE)
- Wake Technical Community College (US)
- Charles River Laboratories (United States) (US)
- Cure Rare Disease, Woodbridge, CT, USA.
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2023-09-28
- Volume
- 389
- Issue
- 13
- Pages
- 1203-1210
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC11288170
- OpenAlex
- W4387077861
- Cited by
- 319
- References
- 26
- Citations by year
- 2026: 80 · 2025: 125 · 2024: 97 · 2023: 17
- FWCI
- 52.96
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (P01HL158506)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Health Sciences › Medicine › Genetics › Neurogenetic and Muscular Disorders Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- Duchenne muscular dystrophy, gene therapy toxicity, acute respiratory distress syndrome, cardiac arrest, diffuse alveolar damage, innate immune response, autopsy
- MeSH terms
- Adult, Antibodies, Humans, Immunity, Innate, Respiratory Distress Syndrome, Genetic Therapy, Dystrophin, Fatal Outcome, Transgenes, Muscular Dystrophy, Duchenne
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