AAV gene therapy for Cockayne syndrome

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, regulation of RNA Pol II mediated transcription repair of oxidative DNA damage, and mitochondrial metabolism. Currently there are no available therapies for these patients. AAV gene therapy offers an opportunity to address this unmet need. We designed a new AAV vector encoding human CSA under a CBA promoter. We tested the therapeutic efficacy of this AAV9-CSA vector by neonatal ICV injection in the Csa ^-/- ;Xpa ^-/- mouse model. Treatment with AAV9-CSA resulted in a significant increase in lifespan, and broad distribution of human CSA in the brain and heart. Despite clear therapeutic benefit, we also observed neuroradiological abnormalities, neuropathologic alterations including hypo-myelination, astrocytosis, microgliosis, and likely life limiting transcriptomic alterations in liver at endpoint. Nonetheless, the success of these experiments paves the way for the first in human clinical translation of a gene therapy for CS patients.