Journal Article

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

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

2023

Overview

We treated a 27-year-old patient with Duchenne’s muscular dystrophy (DMD) with recombinant adeno-associated virus (rAAV) serotype 9 containing d Sa Cas9 (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 1×10 14 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.) A 27-year-old man with Duchenne’s muscular dystrophy who was treated with a CRISPR-Cas9 transgene died from an innate immune response to the high dose of recombinant AAV used for delivery of the transgene.

• Publisher: Massachusetts Medical Society
• Subject: Adult / Alveoli / Antibodies / Antigens / Autopsy / Body weight / Cardiac function / CRISPR / Critical Care / Critical Care General / Drug dosages / Dystrophin / Dystrophin - genetics / Effusion / Enzymes / Epstein-Barr virus / Fatal Outcome / Gene therapy / Genetic Therapy - adverse effects / Genetic Therapy - methods / Genetics / Genetics General / Genomes / Humans / Immunity, Innate - genetics / Immunity, Innate - immunology / Kinases / Lymphocytes T / Magnetic resonance imaging / Muscular dystrophy / Muscular Dystrophy, Duchenne - genetics / Muscular Dystrophy, Duchenne - therapy / Neurology / Neuromuscular Disease / Neurosurgery / Nuclease / Patients / Pulmonary / Respiratory distress syndrome / Respiratory Distress Syndrome - etiology / Respiratory Distress Syndrome - immunology / Scoliosis / Transgenes / Transgenes - genetics / Transgenes - immunology