# AAV-mediated gene therapy demonstrates phenotypic rescue in a mouse model of Cockayne syndrome

Article · 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

- Archive id: doi:10.1172/jci196689
- Published: 2026-07-30
- Venue: The Journal of clinical investigation
- DOI: https://doi.org/10.1172/jci196689
- PMID: 42531030
- PMCID: PMC13574149
- Citations: 0
- Source URL: https://doi.org/10.1172/jci196689
- PDF: https://europepmc.org/articles/PMC13574149/pdf
- Provenance: europepmc

## 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 reproduced under CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)._

Topics: [Gene & Cell Therapy](https://space-kitty.com/topics/gene-cell-therapy)

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