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Directed evolution yields an engineered β-glucocerebrosidase capable of overcoming intrinsic limitations of the wild-type protein

Gaucher disease (GD) is caused by mutations causing a deficiency in the activity of β-glucocerebrosidase (GCase), leading to the lysosomal accumulation of glucosylceramide and glucosylsphingosine in macrophages and neuronal cells. Type 1 Gaucher patients exhibiting peripheral disease are treated with enzyme replacement therapies that ameliorate many manifestations of the disease, but there is a clear unmet need in neuronopathic GD2 and 3, as well as opportunities for improved outcomes for GD1 patients.

We applied the CodeEvolver® directed evolution platform to generate more stable and efficacious GCase variants as potential next generation treatments. In this poster we characterize the improvements in expression and stability of our evolved GCase variants and demonstrate enhanced activity and efficacy compared to wild-type GCase when delivered as an AAV gene therapy in a mouse model of GD.