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

ABSTRACT:

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 cannot 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 an adeno-associated virus (AAV-BR1) encoding the Npc2 gene could cure neurological symptoms in Npc2-/- mice through transduction of BECs, and possibly neurons via viral passage across the BBB.

Methods

SUBMITTER: Rasmussen CLM 

PROVIDER: S-EPMC11786545 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature