Recent Gaucher disease (pronounced go-SHAY) studies are helping us learn more about the genetics of the disease and how it works within the body. Ultimately, this research may open up new options for Gaucher disease treatment.
Ambroxol chaperone therapy for neuronopathic Gaucher disease: A pilot study.
Narita A, Shirai K, Itamura S, Matsuda A, et al. Ann Clin Transl Neurol. 2016 Feb 2;3(3):200-15.
Gaucher disease (GD) is a lysosomal storage disease characterized by a deficiency of glucocerebrosidase. Although enzyme-replacement and substrate-reduction therapies are available, their efficacies in treating the neurological manifestations of GD are negligible. Enzyme-enhancement therapy (EET), which attempts to increase the residual function of enzymes, is a potential future therapy for GD. In EET, pharmacologic or chemical chaperones are used to stabilize the folding of mutant glucocerebrosidase or decrease its degradation. Specifically, a mucolytic agent has been proposed as a candidate pharmacologic chaperone.
Ambroxol, a mucolytic agent has been proposed as a candidate pharmacologic chaperone. In an open-label pilot study, five patients with neuronopathic GD received high-dose oral ambroxol in combination with enzyme replacement therapy. Patients on this combination therapy significantly increased lymphocyte glucocerebrosidase activity and decreased glucosylsphingosine levels in the cerebrospinal fluid. Myoclonus, seizures, and pupillary light reflex dysfunction improved in all patients. Relief from myoclonus led to recovery of gross motor function in two patients who subsequently regained walking ability. These data suggest pharmacological chaperone therapy with high-dose oral ambroxol is promising in treating neuronopathic GD, but additional studies are needed.
Combined beta-glucosylceramide and ambroxol hydrochloride in patients with Gaucher related Parkinson disease: From clinical observations to drug development.
Yuval, Ishay, Ari Zimran, Jeffrey Szer, et al. Blood Cells, Molecules, and Diseases: Volume 68, February 2018, Pages 117-120
Enzyme enhancement therapy (EET) offers a novel therapeutic strategy to increase the residual function of mutant proteins. EET employs small molecules as ‘pharmacological chaperones’ to rescue misfolded and/or unstable mutant enzymes or proteins that have residual function. EET, in conjunction with enzyme replacement therapy, also offers the possibility of treating neurodegenerative lysosomal disorders since these small therapeutic molecules may cross the blood-brain barrier.
Patients with non-neuronopathic Gaucher disease (GD) and heterozygous GBA mutation carrier are at increased risk for Parkinson disease (PD). The risk for PD in these groups does not linearly increase with glucosylceramide (GC) accumulation or with acid glucocerebrosidase (GCase) activity. This observation suggests the possibility that extra-cellular GC actually has beneficial, anti-inflammatory properties; thus, supplementary oral GC administered to GBA carriers at risk for PD may slow inflammatory-driven secondary neuronal death. Ambroxol hydrochloride, a pharmacological chaperone, which reduces endoplasmic reticulum (ER) stress induced by accumulation of mutant misfolded GCase could serve as such an agent. This group proposed that the efficacy of this combined therapy should be evaluated in clinical trials.
Genetic Research on Gaucher Disease
Gaucher disease results from a mutation on the glucocerebrosidase (GCase) gene, causing low GCase enzyme activity. GCase enzyme breaks down glucocerebroside, a fatty chemical that builds up in the bodies of patients with Gaucher disease.
New research on the genetics of Gaucher disease and the GCase gene are helping scientists understand how and why the disease affects patients differently. Key insights include:
- Number of mutations: Researchers have identified almost 300 mutations of the glucocerebrosidase (GCase) gene. The variety of mutations may be part of the reason why Gaucher disease affects people so differently.
- Disease variability: Symptoms of Gaucher disease vary widely, even among identical twins with the same genetic mutation. Researchers think that other processes in the body may determine disease onset, severity and progression.  For example, studies show that certain recycling processes in the cell can affect the buildup of abnormal proteins linked with Gaucher’s disease and associated conditions.
- Parkinson disease link: Like Gaucher disease, some patients with Parkinson disease also have mutations in their GCase gene. Mutations in this gene may increase the risk of both Parkinson and Lewy body dementia (LBD). Learn more about Gaucher and Parkinson disease research.
The Role of Protein Activity in Gaucher Disease
Gaucher disease is one of the most common lysosomal storage disorders. Lysosomes are the body’s recycling centers, breaking down chemicals for reuse as well as waste products. A key role of lysosomes is to recycle proteins, which the body uses in many critical processes.
One protein called alpha-synuclein works with the GCase enzyme and is essential for normal cell function. Studying this protein helps researchers better understand how the disease works, the first step in developing new therapies. Recent findings include:
- Balance of GCase enzyme and alpha-synuclein: The balance of GCase enzyme and alpha-synuclein may play a critical role in helping the body’s proteins work correctly. Too much alpha-synuclein may prevent the GCase enzyme from breaking down glucocerebroside.
- Improper protein folding: Lab studies show a buildup of improperly folded alpha-synuclein in cases of low GCase enzyme levels. Proteins work like a lock and key, with a unique 3-D structure that lets them connect to drugs and other molecules in the body. When proteins are not folded correctly, it is like filling up a keyhole with glue. The abnormal folding of alpha-synuclein causes the proteins to clump together so they cannot do their job.
- Parkinson link: Abnormally folded alpha-synuclein may be an early trigger for Parkinson disease. It is often found in patients with Parkinson disease or LBD who also have a GCase gene mutation. The accumulation of abnormal proteins degrades neurons (brain cells) so they stop working correctly. Learn more about Gaucher and Parkinson disease research.
How Gaucher Disease Research May Lead to New Treatments
Researchers are investigating new approaches to Gaucher disease treatment. These include:
- Reducing glucocerebroside: Scientists are screening large numbers of molecules (chemical compounds) to see which ones can lower glucocerebroside in the body. If they are successful, their results could lead to new drugs or add to current therapies. Ideally, researchers will identify a drug that can cross the blood-brain barrier, which acts to protect the brain but also filters out medications. If they are successful, it could open up treatment options for Gaucher disease types 2 and 3.
- Using chaperone agents: Chaperone agents are drugs that keep proteins properly folded so they can work correctly and help GCase break down glucocerebroside. Chaperone drugs also help drugs hit their target by escorting glucocerebroside to the lysosome where GCase can break it down.
- Treating Gaucher disease types 2 and 3: Lab studies in mice with symptoms of Gaucher disease types 2 and 3 show that decreasing the function of a protein called RIPK3 improved symptoms. However, more work needs to be done to find chemical compounds that will provide the same result in humans.
Gene Therapy, Bone Marrow Transplant and Stem Cell Transplant
Gene therapy involves transplanting normal genes in place of defective ones. Some researchers are looking at gene therapy, but it has been a slow process. As researchers discover how gene therapy helps other genetic diseases, this work may provide new insights into Gaucher disease treatment.
Some researchers are also investigating therapies like bone marrow and stem cell transplant. While these techniques are becoming safer, they are typically rejected for patients with Gaucher disease. The main reason is because the risks outweigh any potential benefits, with current therapies being more effective.
How to Find Gaucher Disease Research Online
If you are interested in finding studies published on Gaucher disease, several online databases are available. Some research papers are available for free, while others will require purchase to view the full text. In most cases, you will be able to view any paper’s abstract (summary) for free.
Places you can look for published research on Gaucher disease include:
 Sidransky E. Gaucher Disease: Insights from a Rare Mendelian Disorder. Discovery Medicine. 2012;14(77):273-281.
 Lopez G, Sidransky E. Predicting parkinsonism: New opportunities from Gaucher disease. Molecular Genetics and Metabolism. 2013;109(3):235-6.
 Siebert M, Sidransky E, Westbroek W. Glucocerebrosidase is shaking up the synucleinopathies. Brain. 2014;137(5):1304-22.
 Nalls MA, Duran R, Lopez G, et al. A Multicenter Study of Glucocerebrosidase Mutations in Dementia With Lewy Bodies. JAMA Neurology. 2013;70(6):727-735.
 Vitner EB, Salomon R, Farfel-Becker T, et al. RIPK3 as a potential therapeutic target for Gaucher’s disease. Nature Medicine. 2014;20:202-208.