Gene expression levels in the central nervous system following intrathecal AAV-mediated gene therapy in dogs with CLN2 neuronal ceroid lipofuscinosis
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[EMBARGOED UNTIL 12/01/2026] CLN2 disease is a pediatric neurodegenerative disorder caused by mutations in the TPP1 gene resulting in a deficiency of the soluble lysosomal enzyme tripeptidyl peptidase-1 (TPP1). The disease is characterized by progressive cognitive and motor decline, brain atrophy, seizures, visual impairment associated with retinal degeneration, and typically culminates in death by the early teenage years. Canine CLN2 disease is a naturally occurring disorder caused by a mutation in the orthologous TPP1 gene and follows a similar progression over a compressed time scale. Gene therapy is being explored as a potential one-time treatment option to combat CLN2 disease. Previous studies have shown adeno-associated virus (AAV) to be a safe and efficient vector for gene therapy; however, it is important to investigate biodistribution of transduction. RT-qPCR allows high sensitivity transcript detection as well as relative quantification. In this project, we used RT-qPCR to measure hTPP1 expression after intravitreal and intrathecal administration of AAV.hTPP1 gene therapy in CLN2-affected dogs to assess the biodistribution of transgene expression in target and off-target tissues. Treatment variables included AAV serotype, treatment age, and dosage. Dogs that received intrathecal injection showed widespread expression in both brain and visceral tissue with no expression seen in eye tissues. Treating dogs at a young age with AAVrh10 resulted in the highest expression in most brain regions. Dogs that received intravitreal injection exhibited more localized transduction with expression specific to the eyes. Assessment of biodistribution with different therapeutic strategies enables identification of the combination of variables that will lead to the greatest transgene expression in the target tissues. Data suggests that for optimal therapeutic benefit, a combined intrathecal, intravitreal, and intravenous administration of gene therapy may be necessary.
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M.S.