• Angela Lek, Brenda Wong, Allison Keeler, Meghan Blackwood, Kaiyue Ma, Shushu Huang, Katelyn Sylvia, A Rita Batista, Rebecca Artinian, Danielle Kokoski, Shestruma Parajuli, Juan Putra, C Katte Carreon, Hart Lidov, Keryn Woodman, Sander Pajusalu, Janelle M Spinazzola, Thomas Gallagher, Joan LaRovere, Diane Balderson, Lauren Black, Keith Sutton, Richard Horgan, Monkol Lek, and Terence Flotte.
• From the Department of Genetics, Yale School of Medicine, New Haven (A.L., K.M., S.H., K.W., S. Pajusalu, M.L.), and Cure Rare Disease, Woodbridge (R.H.) - both in Connecticut; the Departments of Pediatrics (B.W., A.K., R.A., D.K., T.F.) and Neurology (A.R.B.) and Horae Gene Therapy Center and the Li Weibo Institute for Rare Diseases Research (A.K., M.B., K. Sylvia, A.R.B., R.A., D.K., S. Parajuli, T.G., T.F.), University of Massachusetts Chan Medical School, Worcester, the Department of Pathology (J.P., C.K.C., H.L.), the Division of Genetics (J.M.S.), and Department of Cardiology (J.L.), Boston Children's Hospital, and Harvard Medical School (J.P., C.K.C., H.L.), Boston, and Charles River Laboratories, Wilmington (L.B., K. Sutton) - all in Massachusetts; the Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu (S. Pajusalu), and the Genetics and Personalized Medicine Clinic, Tartu University Hospital (S. Pajusalu) - both in Tartu, Estonia; and Regulatory Innovation, Raleigh, NC (D.B.).
• N. Engl. J. Med. 2023 Sep 28; 389 (13): 120312101203-1210.

AbstractWe 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.).Copyright © 2023 Massachusetts Medical Society.

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