Treatments and Disease Management

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).

A massive reduction in spleen (white) size was reported in patients under the treatment of enzyme replacement therapy. Source: Barton 1991
A massive reduction in spleen (white) size was reported in patients under the treatment of enzyme replacement therapy. Source: Barton et al. 1991

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.

Gene Therapy

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).

Drug Molecules

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).

Original Figure
Original Figure by Zachary Shuler. This figure represents the various treatment options for Gaucher’s Disease that have been explained above. Clicking on this figure will allow the reader to view it in an enlarged form in order to read the text. Cellular components affected by the treatment option are highlighted. Sources: Dvir et al. 2003, Tan et al. 2014, and ChemDraw image provided by Dr. Keri Colabroy of Muhlenberg College.

For concluding remarks about Gaucher’s Disease, visit the following page:

Conclusions and Proposals for Future Work

6 Replies to “Treatments and Disease Management”

  1. Hi Zach,
    I am wondering about the side effects of inhibiting GlcCer synthase. These sphinglipid are integral to myelin sheaths etc. Is that the source of the negative side effects?

    1. Hi Dr. C – Due to the fact that GlcCer is involved in a wide range of cellular processes and is the precursor to many different types of sphingolipids [KEGG pathway search], total inhibition of GlcCer synthase would be very problematic. However, the GlcCer synthase inhibitors are partial inhibitors of GlcCer synthase, only to the degree that dysfunctional GlcCerase can clear the accumulations. The genotype of the Gaucher patient also comes into play – a homozygous recessive patient would have a much more defective GlcCerase than a heterozygous carrier. I used the following paper to help me answer your question: Diaz-Font et al. 2006 doi: 10.1016/j.bcmd.2006.07.002. Thanks!

  2. Hi Zach! I thought this section was particularly well done because it investigated the treatment of Gaucher’s Disease on a number of different levels. I was wondering if there were any known dietary restrictions of people diagnosed with Gaucher’s Disease. Do you think that minimizing a patient’s overall intake of glucose would have any effect on the disease state or the disease progression? Since glycosphingolipids are dervied from glucose, or its related metabolites, I could imagine that there would be less of a build-up of GlcCer’s substrate simply because the starting materials are not as abundant. I am aware that there is a steady concentration of glucose in the body even under a ketogenic diet, but I am wondering if, at least, the progression of Gaucher’s Disease would be slowed under these conditions. Is there a possibility for dietary restrictions to be used in conjunction with some of the other available treatment options? Thanks!

    1. These are interesting thoughts, Matt. One of the side effects of the enlarged liver and spleen is that it exerts pressure on the stomach. This often leaves patients with Gaucher’s Disease feeling very full even after eating a limited amount of food. I have read that physicians often recommend diets high in calcium to combat the effects the GD has on bones (I did not focus too much on these symptoms in my website). I have not seen anything about glucose restriction, but it is a good thought. Possible reduced fat intake would be helpful as well, since GD is a sphingolipidosis. To my knowledge, dietary restriction does not seem to be a major avenue for treating or preventing GD. Thanks!


    Your figures were all very informative and strongly reinforced your discussion. The one of the little girl with the inflated stomach was disturbing and at the same time powerful in capturing the attention of the audience; well played. You need to tell me something bad about enzyme replacement therapy.. After reading your description of that treatment i thought, ‘Fantastic, they’ve got a cure figured out!’ but if that treatment was so incredibly successful, why are we looking into other forms of therapy. With that being said, I need to hear about negative side effects or the like… there’s something you’re not telling us.

    Have you come across any type of combination therapy? I could see how the removal of protein degradation factors and enzyme replacement therapy could compliment one another nicely. There could be a 50/50 mix, where we go in and remove the degradation factors so that the remaining GlcCerase comes out functional and those that are already compromised could be removed and replaced. What do you think?

    I’m excited to hear your thoughts. Your time and effort into this project are definitely noticeable. Great work!

    p.s. don’t tell zach #2 we have a numbering system for the zachs… and if you do, don’t tell him he’s #2. i don’t think he’d like that very much. -__-

    1. I’m glad you enjoyed my page, Ryan! There are actually a few complications with enzyme replacement therapy, and this treatment does not work to the same extent in every patient. Here are a few issues: 1) The body may amount an immunological defense against the “foreign” enzyme. It is possible that the body could recognize the new/functional GlcCerase as a pathogen. 2) Even if functional GlcCerase is administered, there are still cells in the body that contain defective GlcCerase and will divide through mitosis, producing even more cells with defective GlcCerase. 3) Enzyme replacement therapy requires large amount of stable enzyme, and human sources are usually preferable. It may be difficult to acquire a large amount of functional GlcCerase that fits these qualifications. With that being said, ERT is often used in combination with other therapies, as you suggested. Combination therapies are used quite frequently, as they are in many other diseases. Take cancer for example – often times, radiation, chemotherapy, and diet supplementation are used at the same time. I hope this answers your questions – thanks for your thoughts!

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