Background: Mutations in the GBA1 gene result in deficiency of β-Glucocerebrosidase (GCase) and cause Gaucher disease Type 1 (GD1). Enzyme replacement therapy (ERT) and substrate reduction therapy currently are standard of care for the treatment of GD1. However, significant unmet needs remain; frequent intravenous (IV) infusion is required because of the short half-life of ERTs. A liver-directed, adeno-associated virus (AAV)-mediated gene therapy may address unmet needs for GD patients by providing sustained, endogenous production of GCase following a single IV infusion. Here we report preclinical characterisation of FLT201, an investigational liver-directed AAV gene therapy for the treatment of GD1.

Method: FLT201, an investigational gene therapy for the treatment of GD1, is a novel, potent, engineered AAV capsid (AAVS3) containing an expression cassette with a novel GBA1 variant (GBA1_var85) that encodes for GCase variant 85 (GCase_var85) protein. The potency and functionality of GCase_var85 when secreted by the liver following treatment with AAV8 expressing GBA1_var85 were evaluated in wild-type (WT) mice, GCase-deficient mice and non-human primates (NHPs; rhesus macaque). In mouse studies, GBA1_var85 was compared to treatment with velaglucerase alfa.

Results: A single infusion of AAV8 expressing GBA1_var85 to WT mice produced robust expression of human GCase in the liver, and a linear dose-dependent and sustained increase in GCase levels in the bloodstream. GBA1_var85 resulted in a steady-state level of GCase uptake into all tissues analysed (liver, spleen, bone marrow and lung). In contrast, administration of velaglucerase alfa resulted in uptake of GCase in spleen and bone marrow, but not in lung tissue. In GCase-deficient mice, GBA1_var85 fully restored GCase activity, and resulted in clearance of substrate, in all tissues analysed (liver, spleen, bone marrow and lung). In contrast, ERT had little effect on levels of substrate (hexosylsphingosine) compared with untreated controls. In NHPs, a single infusion of FLT201 was well tolerated and resulted in rapid and sustained increases of GCase in plasma.

Conclusions: Results of preclinical studies of FLT201 suggest that it has the potential to address areas of current unmet need in GD1 patients. A Phase 1/2 clinical trial of FLT201 in GD1 patients is planned for 2021.