AAV-delivered PPT1 provides long-term neurological benefits in CLN1 mice and achieves therapeutic levels in sheep brain

CLN1 disease is a fatal neurodegenerative condition caused by deficiency in palmitoyl-protein thioesterase 1 (PPT1), for which no disease-modifying therapy exists. The disease affects the entire central nervous system (CNS), necessitating widespread delivery of therapeutics to the brain and spinal cord. Adeno-associated virus (AAV)-based PPT1 gene therapy delivered intrathecally has been tested in mouse models but has shown limited efficacy due to inadequate brain bioavailability. Here, to maximize therapeutic benefit, PPT1 was engineered for improved cross-correction capabilities, packaged in Spark100, a neurotropic AAV capsid, and administered through intracerebroventricular route in neonatal Ppt1 ^−/− mice. This achieved sustained expression of PPT1 protein across the CNS, including key disease-relevant structures, for up to 15 months. It resulted in long-term therapeutic benefits, such as extended lifespan, preserved neurobehavioral function, and prevention of neuropathology, making treated Ppt1 ^−/− mice nearly indistinguishable from wild type. A translatability study in healthy adult sheep, assessing biodistribution of therapeutic in a large and fully developed brain, showed widespread CNS transduction and PPT1 expression with no adverse effects. These studies demonstrate the potential of this approach for treating CLN1 disease and suggest that a similar platform, using a secreted therapeutic protein, might apply to other neurological disorders with broad CNS deficits.