There are multiple avenues that can be utilized for the treatment of Gaucher’s Disease. Some of the treatment types include enzyme replacement therapy, removal of protein degradation factors in the endoplasmic reticulum, gene therapy, inhibition of substrate accumulation, and drug molecules. Each of these treatment options will be explained in turn.
Enzyme Replacement Therapy
Enzyme replacement therapy is the most popular strategy for treating Gaucher’s Disease and has been proposed since 1966, just one year after the molecular basis of Gaucher’s Disease was discovered. The name follows the logic – replacing defective GlcCerase with properly functioning GlcCerase causes the accumulation of GlcCer to decrease. A 1991 study was published in the New England Journal of Medicine that evaluated the effectiveness of enzyme replacement therapy (Barton et al. 1991). Intravenous administration of placental functional GlcCerase into Gaucher patients was performed and its effectiveness was evaluated among many symptomatic parameters – hemoglobin levels increased, acid phosphatase levels decreased, GlcCer levels decreased, organ size decreased, and slight skeletal improvement was observed (Barton et al. 1991). The Gaucher Registry performed a larger statistical sampling study in 2012 to evaluate the effectiveness of enzyme replacement therapy (Weinreb et al. 2013). This study corroborated and compiled the results of various other studies – all of the tested symptoms of Gaucher’s Disease were improved through the utilization of enzyme replacement therapy (Weinreb et al. 2013).
Removal of Protein Degradation Factors
Removal of protein degradation factors in the endoplasmic reticulum (the site of GlcCerase synthesis) could prove to be a useful treatment for Gaucher’s Disease. Protein degradation factors in the endoplasmic reticulum are proteins that can interact with other proteins being synthesized and can have drastic effects on proper folding and trafficking throughout the cell (Tan et al. 2014). A recent study by Tan et al. identified a GlcCerase protein degradation factor that interfered with the folding of GlcCerase (Tan et al. 2014). This protein degradation factor (ERdj3) was first identified through immunoprecipitation with GlcCerase, and its inhibition resulted in increased folding, proper trafficking, and function of GlcCerase. Addition of the pro-folding agent calnexin enhanced the proper folding of GlcCerase (Tan et al. 2014). These scientists are hopeful that inhibiting ERdj3 could be useful in a combinational therapy for the treatment of Gaucher’s Disease.
Implementation of gene therapy for the treatment of Gaucher’s Disease is a process that has not come to full fruition as of yet, but may serve as a viable option for patients who are unresponsive to enzyme replacement therapy. The logic of a genetic approach to treating Gaucher’s Disease is that if a functional GlcCerase can be produced, it can partially alleviate the accumulating GlcCer, which is the stemming point of Gaucher symptoms. Dahl et al. very recently utilized self-inactivating safe lentiviral vectors with strong promoters for the GBA gene (Dahl et al. 2015). The implementation of this lentiviral vector into mice resulted in the reversal of Gaucher symptoms, such as sphenomegaly, liver size, and the presence of Gaucher cells due to a properly folded GlcCerase with an activity level required to clear accumulating GlcCer (Dahl et al. 2015). This treatment method holds promise for future clinical application.
Inhibition of Substrate Accumulation
The symptoms of Gaucher’s Disease stem from high concentrations of GlcCerase substrate (GlcCer), which is a result of a defective GlcCerase. Studies have shown that inhibiting an enzyme that synthesizes GlcCer, glucosylceramide synthase (GlcCer synthase), could prove useful in the treatment of Gaucher’s Disease (Lee et al. 1999). Logically, inhibiting GlcCer synthase reduces the activity of the enzyme and would decrease the concentration of the synthesized product GlcCer. Lee et al. have synthesized a compound that inhibits GlcCer synthase in a more efficient fashion than previous inhibitors (Lee et al. 1999). PDMP homologues have been shown to be potent inhibitors of GlcCer synthase. The addition of various electron-donating substituents of phenyl group moieties greatly enhanced the effectiveness of the PDMP inhibitor (Lee et al. 1999). Not only did the enhanced PDMP inhibitor bind to GlcCer synthase with higher affinity, it reduced GlcCer synthase’s ability to synthesize GlcCer to the greatest extent (Lee et al. 1999).
As an extension of the previous section, drug molecules used for the treatment of type I Gaucher’s Disease have been recently approved by the FDA. There are only two drug molecules that have been approved – Cerdelga and Zavesca. Cerdelga was approved by the FDA in late 2014 and acts as a GlcCer synthase inhibitor, as previously described. Both of these drug molecules structurally resemble ceramide, the substrate of GlcCer synthase, and consequently reduce the buildup of GlcCer (Sinha 2014). In clinical trials, Zavesca exhibited more severe side effects than Cerdelga, so Zavesca is only recommended for those who are ineligible for enzyme replacement therapy (Sinha 2014).
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