Unexpected Death of a Duchenne Muscular Dystrophy Patient in an N-of-1 Trial of rAAV9-delivered CRISPR-transactivator

An N-of-1 trial was developed to deliver a dCas9-VP64 transgene designed to upregulate the cortical dystrophin as a custom therapy for a Duchenne muscular dystrophy (DMD) patient. After showing signs of mild cardiac dysfunction and pericardial effusion, the patient acutely decompensated and sustained cardiac arrest six-days after dosing and succumbed two-days later. Post-mortem examination revealed severe acute-respiratory distress syndrome with diffuse alveolar damage. Vector biodistribution data was obtained and revealed minimal expression of transgene in liver. There was no evidence of AAV9 antibodies nor of effector T cell reactivity. These findings demonstrate innate immune signaling with capillary leak as a form of toxicity in an advanced DMD case treated with high-dose rAAV gene therapy. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial IND28497 [NCT05514249][1] ### Funding Statement This study was funded by the 501c3 foundation Cure Rare Disease. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The protocol was reviewed and approved by the UMass Chan Medical School Institutional Review Board (IRB), Institutional Biosafety Committee, and Center for IRB Intelligence (CIRBI). External safety oversight was provided by an independent data safety monitor. The study was approved by the Food and Drug Administration (IND 28497). Families gave written informed consent for the study. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT05514249&atom=%2Fmedrxiv%2Fearly%2F2023%2F05%2F18%2F2023.05.16.23289881.atom