362. Translatable Gene Therapy for Infantile Neuronal Lipofuscinosis (2016)

Infantile Neuronal Ceroid Lipofuscinosis (INCL) is a rare lysosomal storage disease caused by mutations in the CLN1 gene, which encodes the protein palmitoyl-protein thioesterase-1 (PPT1). In the absence of the PPT1 enzyme, osmiophilic granules accumulate in cells, eventually leading to cell dysfunction and neurodegeneration. In the classic form in human patients, the damage from the storage material and resulting cell death causes visual failure, speech and motor deterioration, and seizures to appear between the ages of 6 and 24 months, with premature death, usually between 3 to 5 years of age. INCL mice (CLN1 knock-out) accurately model the disease symptoms and pathogenesis, leading to premature death at approximately 8 months of age. Previous results from Mark Sands’ laboratory have shown that intracranial administration of AAV5 vectors in newborn INCL mice results in a significant extension of lifespan of approximately 50% along with improvements in motor function. While encouraging, the translation of this approach in humans is complicated by the reduced relative biodistribution of the vector after intracranial administration when moving from a rodent to human brain, and because a newborn mouse corresponds to a prenatal time period in humans. With the ability of AAV9 to cross the blood-brain barrier, intravenous (IV) administration of the vector can achieve widespread distribution of the transgene in the Central Nervous System (CNS), while intrathecal (IT) administration of AAV9 vectors into the cerebrospinal fluid (CSF) can achieve a similar CNS distribution at a considerably lower dose more amenable to human translation. Currently, self-complementary AAV9 vectors are being used in ongoing Phase I human clinical trials for Spinal Muscular Atrophy, administered IV (NCT02122952), and for Giant Axonal Neuropathy, administered IT (NCT02122952). We have pursued two global and translationally-relevant gene transfer approaches for INCL: IT delivery of scAAV9/CLN1 into the CSF of the lumbar cistern at a dose of 7×1010 vg per mouse, and IV delivery of scAAV9.47/CLN1, a liver-detargeted vector, at a dose of 1×1012 vg per mouse. Both approaches were evaluated at different ages: 1 week and 4 weeks (pre-symptomatic), 20 weeks (early-symptomatic) and 26 weeks (post-symptomatic). While we failed to rescue mice injected at 20 weeks or later, mice treated at 1 and 4 weeks of age increased their survival to approximately twice their expected lifespan (ongoing), concurrent with improvement of their quality of life. These results will be compared to a cohort of mice injected as neonates, which are alive at 1 year and being monitored for long-term benefits. Our results indicate that, at the current doses, either treatment approach is effective early in the disease course, providing a dramatic survival benefit and improved quality of life, but it is wholly ineffective once significant symptoms have emerged. The IT route offers a comparable rescue at < 1/10 the dose, making this approach potentially more favorable for human translation. We propose this as a realistic and readily translatable approach to treat INCL.