Cited by 320Virus-based gene therapy researchNeurogenetic and Muscular Disorders ResearchRNA Interference and Gene Delivery

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Death after High-Dose rAAV9 Gene Therapy in a Patient with Duchenne’s Muscular Dystrophy

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Lek, Angela, Wong, Brenda, Keeler, Allison, Blackwood, Meghan, Ma, Kaiyue, Huang, Shushu, Sylvia, Katelyn, Batista, A. Rita, Artinian, Rebecca, Kokoski, Danielle, Parajuli, Shestruma, Putra, Juan, Carreon, C. Katte, Lidov, Hart, Woodman, Keryn, Pajusalu, Sander, Spinazzola, Janelle M., Gallagher, Thomas, LaRovere, Joan, Balderson, Diane, Black, Lauren, Sutton, Keith, Horgan, Richard, Lek, Monkol, Flotte, Terence·2023·New England Journal of Medicine

DOI 10.1056/nejmoa2307798PMC PMC11288170

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Abstract

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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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: Lek, Angela
Wong, Brenda
Keeler, Allison
Blackwood, Meghan
Ma, Kaiyue
Huang, Shushu
Batista, A. Rita
Parajuli, Shestruma
Putra, Juan
Carreon, C. Katte
Lidov, Hart
Woodman, Keryn
Pajusalu, Sander
Spinazzola, Janelle M.
Gallagher, Thomas
LaRovere, Joan
Lek, Monkol
Flotte, Terence
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
DOI: 10.1056/nejmoa2307798
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 (clinical) › 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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Death after High-Dose rAAV9 Gene Therapy in a Patient with Duchenne’s Muscular Dystrophy

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