LAUSR

Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) is a lysosomal storage disease caused by an autosomal recessively inherited mutation in the CLN3 gene. JNCL is a progressive neurodegenerative disorder in which the central nervous system (CNS) is greatly affected resulting in behavioral issues, vision loss, and other cognitive disabilities. We developed a novel AAV capsid with enhanced tropism for CNS tissue after systemic administration and optimized the CLN3 transgene cassette to improve biodistribution and expression in CNS and somatic tissues. AAV9 was used as a benchmark to assess the gene biodistribution in the Cln3Δex7/8 mice model. AAV9-CLN3 and AAV214-CLN3 were compared in mice that received 2.0 x 1013 vg/kg via intravenous administration. After 30 days the animals were sacrificed and tissues were harvested for biodistribution analysis. We evaluated capsid delivery in the primary regions of the CNS and the spinal cord (cervical and lumbar). In those tissues AAV214-CLN3 showed greater biodistribution efficacy when compared to AAV9-CLN3 (brain=160% of AAV9, Cervical SC=158% of AAV9 and lumbar SC=184% off AAV9). The sciatic nerve also demonstrated higher AAV214-CLN3 (744%) biodistribution compared to AAV9. The optimization of the CLN3 gene and expression cassette along with a novel AAV vector was able to show greater tropism into the CNS via systemic administration. Current studies assessing expression and dose response over a longer duration suggest AAV-214 can be used for effective systemic delivery and the ability to correct CLN3 in CNS tissues and peripheral tissues.