Recombinant Human GBA protein

**Background of Recombinant GBA Protein**

The glucocerebrosidase (GBA) enzyme, encoded by the *GBA1* gene, plays a critical role in lysosomal metabolism by breaking down glucocerebroside into glucose and ceramide. Deficiencies in GBA activity lead to Gaucher disease, a lysosomal storage disorder characterized by the accumulation of glucocerebroside in macrophages, resulting in organ damage, bone abnormalities, and neurological symptoms in severe cases. Historically, treatment relied on enzyme replacement therapy (ERT) using purified human placental GBA, but limited supply and immunological challenges prompted the development of recombinant GBA proteins.

Recombinant GBA is produced via genetic engineering, typically using mammalian cell systems (e.g., Chinese hamster ovary (CHO) cells) to ensure proper post-translational modifications, such as glycosylation, critical for enzyme stability and lysosomal targeting. The first FDA-approved recombinant GBA, imiglucerase (1990s), marked a breakthrough in Gaucher disease management, offering scalable production and reduced immunogenicity. Subsequent iterations, including velaglucerase alfa (produced in human fibroblast cells) and taliglucerase alfa (plant-cell-based expression), further diversified production platforms and improved patient access.

Beyond Gaucher disease, recombinant GBA has garnered interest in Parkinson’s disease research, as *GBA1* mutations are a common genetic risk factor. Preclinical studies explore its potential to mitigate alpha-synuclein aggregation and neurotoxicity. However, challenges persist, including high production costs, short half-life, and limited blood-brain barrier penetration. Innovations like PEGylation, engineered variants with enhanced stability, and gene therapy approaches aim to address these limitations. Overall, recombinant GBA remains a cornerstone of precision medicine for lysosomal disorders, with ongoing research expanding its therapeutic scope.