Fig. 4

Different hypothetical mechanisms by which GCase can be impaired, and various therapeutic approaches targeting these mechanisms. These include A) failure of the GCase protein to exit the ER, B) failure of GCase to link with its LIMP2 trafficking transporter, C) GCase is misfolded and unstable, so degraded through the unfolded protein response, D) failure of GCase to exit the Golgi, E) GCase is inactive due to mutations at the active site, and F) GCase activity is altered due to a Saposin C defect, and. The failure of GCase to reach the lysosome or be activated in the lysosome enables GlcCer and GlcSph to accumulate in the lysosome, creating the hallmark marker of Gaucher disease, Gaucher cells. Various therapies to address GCase impairment include: 1) Gene therapy: directly replacing mutant DNA with corrected DNA via adeno-associated or other viral infection. 2) Pharmacological chaperone therapy: introducing chaperone proteins to stabilize and refold misfolded proteins. 3) Histone deacetylase inhibitors: inhibiting unfolded protein response to allow more misfolded proteins to reach the lysosome. 4) Enzyme replacement therapy (ERT): replacing dysfunctional enzyme with recombinant enzyme targeted to the lysosome. 5) Substrate reduction therapy (SRT): reducing substrate accumulation regardless of GCase levels by inhibiting substrate synthesis. Currently, ERT and SRT are the only FDA-approved treatment options for patients with Gaucher disease