Liver directed AAV gene therapy to treat Gaucher disease

Gaucher disease (GD) is characterised by the deposition of glucocerebroside in cells of the macrophage-monocyte system caused by impaired production of the enzyme beta-glucocerebrosidase (GCase). Over the past 20 years, enzymatic replacement therapy (ERT) was developed as the standard of care for GD. However, since it requires continuous treatment (every other week infusions), it results in a high cumulative cost for this type of therapy, and more importantly in a significant patient treatment burden. Over the same period, gene therapy has emerged as a very promising avenue of treatment for various monogenic genetic disorders, allowing sustained levels of transgene expression upon a single treatment. We hypothesised that liver-directed gene therapy could be used to ameliorate GD disease. For this purpose, we used an adeno-associated viral vector (AAV) to drive the expression of human GBA gene in the liver of mice. Four weeks after a single injection we observed a steady and dose-dependent elevation of GCase in the bloodstream of treated mice. Upon tissue analysis, noticeable uptake of human GCase was observed in organs affected in GD such as spleen, lung and bone marrow. Marker analysis performed in spleen tissue showed positive staining for human GCase in macrophages. Further improvement in our AAV constructs, obtained by applying rational design and codon optimisation algorithms, has allowed us to achieve an additional five-fold increase in GCase circulating in the bloodstream, resulting in increased uptake by macrophages. Overall, these data show that upon a single injection of a liver-expression-directed AAV vector it is possible to achieve elevation of GCase in the bloodstream that results in greater GCase bioavailability compared to current ERT. Therefore, this approach offers enhanced therapeutic potential for the treatment of GD.