Endothelial and neuronal engagement by AAV-BR1 alleviates neurological symptoms and cholesterol deposition in a mouse model of Niemann-Pick type C2

Background Patients with the genetic disorder Niemann-Pick type C2 disease (NP-C2) suffer from lysosomal accumulation of cholesterol causing both systemic and severe neurological symptoms. In a murine NP-C2 model, otherwise successful intravenous Niemann-Pick C2 protein (NPC2) replacement therapy fails to alleviate progressive neurodegeneration as infused NPC2 is unable to cross the blood-brain barrier (BBB). Genetic modification of brain endothelial cells (BECs) is thought to enable secretion of recombinant proteins thereby overcoming the restrictions of the BBB. We hypothesized that BBB-directed gene therapy using the AAV-BR1-NPC2 vector would transduce both BECs and neurons in a mouse model of NP-C2 ( Npc2 -/-). Methods Six weeks old Npc2 -/- mice were intravenously injected with the AAV-BR1-NPC2 vector. Post-mortem analyses included gene expression analyses, determination of NPC2 transduction in the CNS, and co-detection of cholesterol with NPC2 in neurons. Results The vector exerted tropism for BECs and neurons resulting in a widespread NPC2 distribution in the brain with a concomitant reduction of cholesterol in adjacent neurons, presumably not transduced by the vector. Conclusion The data suggests cross-correcting gene therapy to the brain via delivery of NPC2 from BECs and neurons.