Intravenous infusion of iPSC-derived neural progenitors expressing GCase ameliorates alpha-synuclein aggregates in a mouse model of Gaucher disease

Abstract

Mutations in GBA1, which encodes the lysosomal acid beta-glucosidase (GCase), cause GCase deficiency in Gaucher disease (GD) and is the most common genetic risk factor for Parkinson disease (PD). There are no effective treatments available for neuronopathic GD and PD that can stop or slow neurodegeneration. In this study, we evaluated a novel non-invasive cell transplantation therapy in a GD mouse model (9H/PS-NA) exhibiting alpha-synuclein aggregation, a key PD-relevant phenotype. A subclass of iPSC-derived neural progenitor cells (NPCs) expresses VLA4 which allows systemically-delivered NPCs to cross the blood-brain-barrier. We established VLA4+ mouse iPSC-derived NPCs harboring lentiviral-mediated overexpression of wild-type human GCase (hGCase). In-vitro, VLA4+ hGCase+ NPCs were expandable without loss of multipotency and secreted GCase which was taken up by lysosomes of adjacent Gba1-null cells. In-vivo efficacy was evaluated in 9H/PS-NA mice. VLA4+ hGCase+ NPCs were intravenously administered by weekly tail-vein injection and mice were analyzed at 14 weeks of age for effects on neuropathic and PD phenotypes. Injected cells engrafted throughout the brain, including thalamus, cortex, brainstem and midbrain, and differentiated into neural lineages. Human GCase protein was detected in the transplanted mouse brains with specific anti-human GCase antibody. Histological analyses of brain sections showed reduced neurodegeneration by Fluoro-Jade C staining in the regions of NPC migration. CNS inflammation, detected by anti-CD68 and anti-GFAP antibodies, was significantly decreased in the brain of transplanted mice. Compared to vehicle treated mice, VLA4+ hGCase+ NPC-transplanted mice showed ~50% reduction of α-synuclein aggregates in the substantia nigra. Together, these results demonstrate the efficacy of non-invasive delivery of iPSC-derived NPCs overexpressing hGCase in GD mouse model and establish the feasibility of combined cell and gene therapy for GBA1-associated PD. This approach provides a potential treatment for both rare and common neurological diseases.