{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T13:25:06Z","timestamp":1790083506295,"version":"4.0.1"},"reference-count":89,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T00:00:00Z","timestamp":1772150400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100025799","name":"American Neuromuscular Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100025799","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: Recombinant adeno-associated virus (AAV) vectors have revolutionized gene therapy for monogenic diseases such as Duchenne muscular dystrophy (DMD). However, high systemic doses required for muscle transduction cause a spectrum of toxicities ranging from transient hepatic inflammation to fatal multi-organ failure leading to death. These adverse events have reshaped the risk\u2013benefit considerations for gene therapy in DMD. Methods: We conducted a narrative review describing complications associated with AAV-mediated gene therapies in the DMD field. PubMed and Clinicaltrials databases were used to search for peer-reviewed manuscripts published between 1987 and 2025. Publicly available abstracts and press releases were also used to describe AAV-mediated adverse events that have been discovered. Priority was given to large prospective cohorts, meta-analyses, and high-impact publications. Results: We outlined the mechanistic basis of AAV toxicity\u2014spanning innate and adaptive immune activation, vector\u2013host interactions, transgene overexpression, and host vulnerability\u2014and discussed their therapeutic implications for DMD. We also highlighted ongoing strategies for vector re-design, immune modulation, patient selection, and regulatory adaptation, aiming to improve efficacy with safety in the next generation of muscular dystrophy gene therapies. Conclusions: Patient safety remains the number one priority in the AAV-mediated gene therapies field. Achieving long-term benefits requires continued optimization of existing vectors, implementation of strict criteria for patient selection, and regulation of immune responses, with close collaboration and transparent dialog among scientists, clinicians, and regulatory agencies, informed by both successful cases as well as tragic deaths reported in the fields of neuromuscular diseases.<\/jats:p>","DOI":"10.3390\/genes17030284","type":"journal-article","created":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T15:52:38Z","timestamp":1772207558000},"page":"284","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Adeno-Associated Virus Toxicity in Duchenne Muscular Dystrophy: Mechanisms and Clinical Considerations"],"prefix":"10.3390","volume":"17","author":[{"given":"Ezgi","family":"Saylam","sequence":"first","affiliation":[{"name":"The Jerry R. Mendell Center for Gene Therapy, Nationwide Children\u2019s Hospital, Columbus, OH 43215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleonora S.","family":"D\u2019ambrosio","sequence":"additional","affiliation":[{"name":"Departments of Neurology, UMass Chan Medical School, Worcester, MA 01655, USA"},{"name":"Departments of Genetic and Cellular Medicine, UMass Chan Medical School, Worcester, MA 01655, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Tozzo","family":"Pesco","sequence":"additional","affiliation":[{"name":"Departments of Genetic and Cellular Medicine, UMass Chan Medical School, Worcester, MA 01655, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5639-442X","authenticated-orcid":false,"given":"Liubov V.","family":"Gushchina","sequence":"additional","affiliation":[{"name":"The Jerry R. Mendell Center for Gene Therapy, Nationwide Children\u2019s Hospital, Columbus, OH 43215, USA"},{"name":"Department of Pediatrics, The Ohio State University, Columbus, OH 43215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1186\/s13023-020-01430-8","article-title":"Global epidemiology of Duchenne muscular dystrophy: An updated systematic review and meta-analysis","volume":"15","author":"Crisafulli","year":"2020","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1038\/s41572-021-00248-3","article-title":"Duchenne muscular dystrophy","volume":"7","author":"Duan","year":"2021","journal-title":"Nat. Rev. Dis. 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