{"id":"doi:10.1172/jci196689","kind":"article","title":"AAV-mediated gene therapy demonstrates phenotypic rescue in a mouse model of Cockayne syndrome","authors":["Batista AR","Scholand AC","Callahan WS","Watson MK","Sion CM","Mola T","O'Hara K","Wentworth SA","Sena-Esteves WS","King OD","King RM","Sena-Esteves M"],"author_count":12,"year":2026,"published":"2026-07-30","venue":"The Journal of clinical investigation","cited_by":0,"doi":"10.1172/jci196689","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1172/jci196689","archive_url":"https://space-kitty.com/papers/doi:10.1172/jci196689","updated":null,"pmid":"42531030","pmcid":"PMC13574149","openalex_id":null,"pdf_url":"https://europepmc.org/articles/PMC13574149/pdf","abstract":"Cockayne syndrome (CS) is an autosomal recessive, progressive developmental and neurodegenerative disease. Approximately 30% of cases are caused by mutations in the ERCC8/CSA gene. Patients with CS present with cutaneous photosensitivity, growth failure, shorter life span, and a progressive degeneration of the central nervous system. Loss-of-function mutations in CSA result in deficiencies in transcription-coupled nucleotide excision repair. Currently, no therapies are available for these patients. Adeno-associated virus-mediated (AAV-mediated) gene therapy offers an opportunity to address this unmet need. We designed an AAV vector encoding human CSA under a ubiquitous promoter. We tested the therapeutic efficacy of this AAV9-CSA vector by neonatal intracerebroventricular injection in the Csa-/- Xpa-/- mouse model. Treatment with AAV9-CSA resulted in a significant increase in life span, and broad distribution of human CSA in the brain and heart, without evidence of vector-related toxicity. Despite clear therapeutic benefit, we also observed neuroradiological abnormalities, and neuropathologic alterations, including hypomyelination, astrocytosis, and microgliosis, as well as likely life-limiting transcriptomic alterations in liver at endpoint. Nonetheless, the success of these experiments paves the way for clinical translation of an AAV gene therapy for patients with CS into humans.","abstract_license":"CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)","license":"CC-BY","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":[],"details":null,"provenance":"europepmc","attribution":"Abstract of \"AAV-mediated gene therapy demonstrates phenotypic rescue in a mouse model of Cockayne syndrome\" by Batista AR, Scholand AC, Callahan WS et al., https://doi.org/10.1172/jci196689, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified.","topics":[{"slug":"gene-cell-therapy","name":"Gene & Cell Therapy","domain_slug":"medicine"}],"cited_in_dossiers":[]}