Niemann-Pick disease, type C1 (NPC1) is a rare neurodegenerative lysosomal storage disease with a wide spectrum of clinical manifestation. Multiple genetic factors influence the NPC1 mouse phenotype, but very little attention has been given to prenatal environmental factors that might have long-term effects on the neuroinflammatory component of NPC1 pathology. Studies in other mouse models of cerebellar ataxia have shown that developmental exposures lead to Purkinje neuron degeneration later in life, suggesting that environmental exposures during development can impact cerebellar biology. Thus, we evaluated the potential effect of maternal immune activation (MIA) on disease progression in an Npc1 mouse model. The MIA paradigm used mimics viral infection using the toll like receptor 3 agonist polyinosinic-polycytidilic acid during gestation. Through phenotypic and pathologic tests, we measured motor and behavioral changes as well as cerebellar neuroinflammation and neurodegeneration. We observed a gender and genotype dependent effect of MIA on the cerebellum. While the effects of MIA have been previously shown to primarily affect male progeny, we observed increased sensitivity of female mutant progeny to prenatal exposure to treatment with polyinosinic-polycytidilic acid. Specifically, prenatal MIA resulted in female NPC1 mutant progeny with greater motor deficits and a corresponding decrease in cerebellar Purkinje neurons. Our data suggest that prenatal environmental exposures may be one factor contributing to the phenotypic variability observed in individuals with NPC1.

Niemann–Pick C1 disease (NPC1) is a rare, fatal neurodegenerative disease caused by mutations in NPC1, which encodes the lysosomal cholesterol transport protein NPC1. Disease pathology involves lysosomal accumulation of cholesterol and lipids, leading to neurological and visceral complications. Targeting the central nervous system (CNS) from systemic circulation complicates treatment of neurological diseases with gene transfer techniques. Selected and engineered capsids, for example, adeno-associated virus (AAV)-PHP.B facilitate peripheral-to-CNS transfer and hence greater CNS transduction than parental predecessors. We report that systemic delivery to Npc1m1N/m1N mice using an AAV-PHP.B vector ubiquitously expressing NPC1 led to greater disease amelioration than an otherwise identical AAV9 vector. In addition, viral copy number and biodistribution of GFP-expressing reporters showed that AAV-PHP.B achieved more efficient, albeit variable, CNS transduction than AAV9 in Npc1m1N/m1N mice. This variability was associated with segregation of two alleles of the putative AAV-PHP.B receptor Ly6a in Npc1m1N/m1N mice. Our data suggest that robust improvements in NPC1 disease phenotypes occur even with modest CNS transduction and that improved neurotrophic capsids have the potential for superior NPC1 AAV gene therapy vectors.

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