The first generation of clinical trials targeting specific genetic subtypes of the Parkinson's population are underway for carriers of GBA and LRRK2 mutations. These trials mark a critical moment in the history of neurology as they are among the first attempts to apply principles of precision medicine to a neurodegenerative disease. However, any new trial of this sort brings with it a degree of uncertainty for everyone involved. So, to try and gain a little more clarity (as a GBA mutation carrier myself), I asked some GBA experts to answer a few questions on the bleeding edge of GBA-PD research. Below are the results.
Author: Benjamin Stecher (GBA-PD patient)
Among the most promising targets in Parkinson’s disease (PD) research today are mutations in the glucosylceramidase beta (GBA) gene. As many as ten percent of people with PD in North America carry one of the known genetic variants of this gene, making it the most common of the identified PD mutations.1
The GBA gene sits close to the middle of chromosome 1 and encodes for a protein 536 amino acids in length called glucocerebrosidase (often referred to as GCase). This protein plays a pivotal role in our lysosome, the recycling unit of cells. GBA mutations tend to decrease the activity of this protein, impairing the ability of lysosome to function properly which may allow for the build-up of harmful accumulations of alpha-synuclein. The prevailing belief in the field is that if we correct the GBA pathway, we might be able to restore healthy lysosomal function in people who have GBA-PD and, in-so-doing, modify the progression of their disease.
But, like most things in neurodegeneration, it’s complicated. Not only are we uncovering more and more GBA mutation variants that might each have slightly different downstream effects, but we also carry more than one GBA gene and have a pseudo-GBA gene (a section of a chromosome that is an imperfect copy of a functional gene) that are far less well understood but which some researchers believe also may impact GCase activity.2,3
The good news for GBA-PD is that we got a head-start on research thanks to Gaucher disease, a lysosomal storage disorder also linked to mutations in the GBA gene. (In Gaucher disease, GCase activity is markedly reduced, thereby pathologically elevating the amount of lipid substrates that the enzyme normally degrades in the macrophage population of cells in affected people’s spleens, bone marrow, livers, brains, etc.) Though treatments for Gaucher disease do not cross the blood–brain barrier, GBA-PD research has been able to piggyback off all the knowledge Gaucher researchers generated about the GBA gene, allowing for the accelerated development of therapeutic interventions for GBA-PD. This has led to a flurry of activity in GBA-PD research and already several clinical trials have begun targeting the GBA pathway. These include:
Sanofi-Genzyme: A drug (named GZ/SAR402671) is being tested that inhibits a lipid (glucosylceramide) thought to build up in people with GBA-PD. Clearing these excess lipid accumulations may prevent alpha-synuclein from clumping and harming brain cells. This drug has recently begun phase 2 clinical trials.4
Lysosomal Therapeutics: The lead drug candidate (LTI-291) is a GCase enzyme activator. It is believed that increasing GCase activity will reduce levels of its harmful substrate, glucosylceramide, thereby restoring healthy lysosomal function.5 It has completed phase 1 clinical trial.
Ambroxol: A repurposed drug commonly used as an anti-mucolytic respiratory medicine. Pre-clinical studies show ambroxol increases GCase function in neurons and improves mitochondrial function, lysosomal biogenesis, and the secretory pathway.6 It is currently in a phase 2 clinical trial.
These trials represent an important historical moment in precision medicine for neurodegenerative disorders as they are among the first drug trials tailored for a subset of the PD population. (Click here for a thorough review of GBA mutations in PD, published in JPD.7)
However, there is still a lot of uncertainty surrounding GBA-PD and these trials. So, to try and get a little more clarity, I surveyed some of the people in the field who know it best.
Prof. Michael Schlossmacher, Director, Neuroscience Program, Ottawa Hospital Research Institute – Co-discovered biochemical links between lysosomal dysfunction and Parkinson’s, including those caused by mutations in GBA1 and cathepsin D.
Dr. Mark R. Cookson, Senior Investigator at National Institute on Aging – Uses genetic information to understand the pathways involved that lead to neuronal damage and death.
Prof. Ziv Gan-Or, Assistant professor at the Neurology & Neurosurgery and the Human Genetics departments at McGill University – Helped characterize the GBA gene in PD and leads G-QUEST, a new GBA-Quebec study group focused on GBA research to facilitate new clinical trials.
Dr. Ellen Sidranksy, Senior investigator in the National Human Genome Research Institute's Medical Genetics Branch – Her group was the first to identify GBA as a risk factor for parkinsonism.
Prof. Roy Alcalay, Assistant Professor at the Movement Disorders Division at Columbia University Medical Center – Led several key studies providing information on the link between GBA mutations and Parkinson.
Prof. Thomas Gasser, Director of the Department of Neurodegenerative Diseases at the Hertie-Institute for Clinical Brain Research and coordinator for clinical studies at the German Center for Neurodegenerative Diseases Tübingen (DZNE) – Principal investigator in MiGAP, studying geno-phenotypic characterization of GBA-associated Parkinson's disease with regard to motor and non-motor symptoms and the identification of specific biomarkers in blood, cerebrospinal fluid and cell models.
Prof. Michela Deleidi, Assistant Professor at the German Center for Neurodegenerative Disease/University of Tübingen – Focuses on the mechanistic pathways involved in GBA1-linked neurodegeneration, with a particular interest in mitochondrial function and autophagy.
Dr. Avner Thaler, Movement Disorders Unit, Neurological Institute, Tel-Aviv Sourasky Medical Center – Studies imaging markers of GBA-PD as well as how different GBA mutations affect the severity of PD.
I asked the experts a series of questions (shown in bold) and the individual responses are shown below each question.
Note: Participants were asked to skip any questions for which they had a conflict of interest.
At the moment, how complete do you think our understanding of GBA-PD is?
Michael Schlossmacher: “Rather incomplete.”
Mark Cookson: “Far from complete! In Gaucher’s disease we can be pretty sure that the net loss of GBA activity is what drives phenotypes in disease given that there is clear loss of function and they are inherited in a recessive manner. But I don’t think we know that for PD and some alternate models other than strict loss of function need to be considered (or at least ruled out). One clue is that there are PD-associated alleles that are not associated with Gaucher’s disease. Logically, these alleles must have enough enzymatic function to prevent Gaucher’s disease, so there must be a reason they cause PD. Complex possibilities such as a partial loss of function combined with some novel gain of function can’t be ruled out. We clearly still have a lot to learn.”
Ziv Gan-Or: “I think that our understanding is far from being complete. The main gaps are in understanding the mechanism by which GBA mutations/deficiency leads to PD. While there are several hypotheses, the picture is not clear at all and a lot more research is necessary.”
Ellen Sidransky: “There are still many gaps in our understanding.”
Roy Alcalay: “The multiple studies on the link between GBA mutations and PD confirm this association is solid. Our understanding of GBA-PD is still incomplete. We do not know how mutations cause PD, and how to de-link GBA and PD to eliminate PD risk in GBA carriers.”
Thomas Gasser: “Hard to say, because we don’t know the “unknown unknowns“. Why, for example, do only a minority of mutation carriers develop disease? As long as we don’t know that, we have serious gaps in our understanding.”
Michela Deleidi: “Despite the growing knowledge of the relationship between GBA and PD, the precise mechanisms related to GBA pathology are not fully understood. Many pathological pathways are likely involved. Among others a-synuclein pathology, lysosomal dysfunction, mitochondrial demise as well as lipid changes and cellular stress have been linked to GBA. How these pathways are interconnected is still unclear. In addition it is not easy to dissect disease drivers and secondary effects to degeneration. Interestingly, GBA also has a role in sporadic PD as well as in brain ageing, suggesting that targeting GBA could be a valuable approach not only for people with GBA mutations. GBA is a risk factor and the majority of GBA mutations carriers do not develop PD. Understanding disease modifiers is one of the major challenges (this is key to genetic counseling.)”
Avner Thaler: “I think we’re getting there, but there are still far more unknowns than knowns. We've established that severe mutations are worse than mild ones when it comes to both risk of PD and severity of phenotype. But we’re not actually sure why. We’re still in the blue regarding influences on penetrance; so much work is still needed.”
Which specific factors do you think might account for the incomplete penetrance of GBA mutations? (Why most GBA mutation carriers will never develop PD)
Michael Schlossmacher: “It is a risk allele, and not to be understood as causative in and by itself.”
Mark Cookson: “I don’t know, but two non-mutually exclusive possibilities are (1) the relative expression of wild type and mutant alleles and (2) whether expression can be upregulated by non-genetic factors. My guess is that if the mutant allele does affect PD risk by a toxic process then the more of it there is (and the less wild type) then the greater the risk of PD.”
Ziv Gan-Or: “Like in most complex diseases, it is genetics and environmental exposure, not necessarily in this order. While we have evidence that additional genetic factors may affect the penetrance of GBA-mutations, it seems that different exposures (for example – different toxins, nutrition, viruses/bacteria etc.) have a larger contribution. However, the study in this field, of understanding the different factors that affect GBA mutations penetrance, is only at very initial stages.”
Ellen Sidransky: “I think aging definitely plays a role, perhaps also lysosomal function in general.”
Roy Alcalay: “We do not know what accounts for the incomplete penetrance of GBA mutations. As in similar cases in medicine, both genetic and environmental factors may contribute to PD risk in GBA carriers. Studies on risk modifiers are an urgent need in the field.”
Thomas Gasser: “See (my answer) above, we have no clue. Variable compensatory capacity, necessity of second hits, environmental or behavioral factors, good or bad luck…”
Michela Deleidi: “Both genetic and environmental disease modifiers can play a key role. We assume that variants at other genetic loci interact with the disease-causing allele and influence its phenotypic expression. To identify genetic variants that might modify the phenotype, it will be necessary to recruit high numbers of PD patients with or without GBA mutations as well as asymptomatic carriers and perform whole-exome or -genome sequencing. This will allow the identification of risk and protective genetic factors. It will be also important to further understand the interaction between GBA and other PD genes. Environmental/lifestyle modifiers can also modify the penetrance and influence GBA biology and function in neuronal and non-neuronal cells.”
Avner Thaler: “I’m sure polymorphisms in many genes are involved in reduced penetrance, as well as environmental, metabolic and inflammatory markers.”
Do you think clinical trials, as they are currently structured, will be able to tell us if a therapy targeting GBA mutations is viable? Why or why not?
Michael Schlossmacher: “Yes, even if unsuccessful, these studies will inform all future precision medicine based trials for PD – Matching a patient and his risk profile with the right target and best suited (drug) intervention.”
Mark Cookson: “Clinical trials have to be taken one by one, and whether each meets its preset outcome or not is only part of the answer about whether a target is viable. I think people will try very hard to understand if the given approach has had its intended effect in the brain, but really showing that is going to be hard. Even then, knowing how soon to intervene and for how long is hard to know ahead of time. I hope that even if initial specific trials fail, GBA targeting therapies would be continued in general.”
Ziv Gan-Or: “The way clinical trials are being done today is very problematic. First, they are based on compounds that were discovered in animal models, typically mice or rats. We know that in the vast majority of cases, compounds that work on mice do not work on humans. Furthermore, clinical trials, when dividing the patients into “treatment” and “placebo” groups, do not take into account the different factors that can affect the rate of progression of disease. For example, there could be two patients, at the exact age, with the exact same GBA mutation, and one of them will progress very rapidly, while the other very slowly. This is not a rare example. If there is an imbalance in terms of rate of progression of the disease between the “treatment” and “placebo” groups, this could result in false negative or positive results. Therefore, we need to understand the different factors that affect the rate of progression of GBA-associated PD, and make sure that the two groups that we are studying are balanced. Furthermore, clinical trials are being done on patients who already exhibit PD symptoms. It means that many of their neurons are already dead or dying. It means that even if the drug is effective, it could be too late. Therefore, we need to make efforts to identify these patients and enroll them into clinical trials at a much earlier phase. This can be done by screening for REM sleep behavior disorder (RBD) for example, which may occur 10 years in average prior to the motor symptoms of PD. We can also screen for other non-motor symptoms in healthy carriers of GBA mutations, such as reduced sense of smell, color discrimination, orthostatic hypotension and others, but RBD is the most sensitive and specific of them.”
Ellen Sidransky: “Clinical trials are a little tricky until we better understand the link. For example, if lipid storage does not play a role, substrate inhibition will not be effective.”
Thomas Gasser: “If we do trials in stratified cohorts and find useful biomarkers for target engagement and measuring progression then I thank we have a good chance.”
Michela Deleidi: “The current clinical trials are targeting GBA or GBA-related mechanisms. GBA-PD patients represent the ideal cohort for precision medicine approaches; results from current clinical trials will instruct future interventions at early disease stage (or even asymptomatic).”
Avner Thaler: “I think the first generation targeted therapies will fail but will supply enough data for better studies in the future. I am skeptical about the possibility of halting PD progression once it is clinically diagnosed, but early detection and treatment might hold promise.”
Do you believe correcting the mutation would reverse, halt or just slow the progression of the disease in most people with GBA-PD?
Michael Schlossmacher: “Entirely speculative, but even slowing the progression would be a significant, first accomplishment.”
Mark Cookson: “I think if we can halt progression of early motor PD, we’ll have had a huge impact on people’s lives and that’s what we should hope for. Reversal of symptoms that are well established seems a bit unlikely, although a laudable goal. The specific issue with non-penetrant mutations is that we’ll be exposing people to some level of risk in the context of gene correction, without knowing for sure what their future holds in terms of whether they manifest motor PD. Despite this reservation, the plus side of gene correction is that we don’t actually have to fully understand mechanism – we just need to know the sequence.”
Ziv Gan-Or: “As explained in my previous answer, today we start treatment at a very late stage. Therefore, I think that in individuals with GBA-PD, correcting the mutation will only slow, at best, the disease progression. It will not reverse the disease process, as neurons that are already dead are not likely to regenerate. If we will be able to correct the mutation at a much earlier stage, perhaps it will halt the disease process.”
Ellen Sidransky: “It depends whether the problem is the mutation or the deficiency of the enzyme. Also if the disease has progressed, reversal may be difficult.”
Roy Alcalay: “This is a great question, and I do not know the answer for it. I can only hypothesize that if correcting the GBA mutation would work on modifying PD risk, the earlier the intervention is made, the better the outcome will be.”
Thomas Gasser: “Depends on when you do it. If late, too much secondary damage, also inducing progressive changes, could have been done, so the earlier the better.”
Michela Deleidi: “Do you mean by gene therapy? (Yes) If this is the case it depends on the time of the intervention, if done early it could even prevent or halt (disease progression). It should not be limited to brain cells though.”
Avner Thaler: “Again I think it depends at what stage we intervene. I am doubtful when it comes to full blown GBA-PD but more hopeful regarding non-manifesting heterozygote carriers.”
Does the heterogeneity of mutations mean that we will need several different GBA targeted therapies?
Michael Schlossmacher: “Could be, it depends on the design of the intervention. Furthermore, likely gain-and loss-of-function events may play a role in distinct mutants associated with PD and DLB risk.”
Mark Cookson: “I think this is possible but unlikely. In general, the key to understanding mutations across a given gene is to identify what all the mutations have in common as it’s those common events that drive a specific disease. The only exception would be if the initial events driving pathogenesis vary somewhat then converge on a downstream target – but in that case I would go for the target downstream.”
Ziv Gan-Or: “This is a likely scenario, and the answer is dependent on which drugs/treatments will be developed. If we are talking about gene therapy, it could be relevant for all mutation types. If we are talking about drugs that act as chaperons for example, they will be relevant only for mutations that impair the trafficking of GBA to the lysosome. We see examples in other diseases in which certain drugs only help carriers with specific mutations, while they do not help carriers of other mutations in the exact same gene and disease. For example, the drug Ivacaftor in cystic fibrosis helps only for carriers of a few mutations out of the >1000 mutations that exist in the CFTR gene and cause cystic fibrosis.”
Ellen Sidransky: “Still not clear.”
Roy Alcalay: “Many proposed interventions for GBA-PD may work for all mutations alike (e.g. gene therapy). However, an alternative intervention would be to use small molecules called chaperones, which stabilize the enzyme encoded by GBA, glucocerebrosidase (GCase). Chaperones may bind more strongly to some variants of the mutant GCase enzyme than to others. In this case, it is possible that more than one chaperone would be required.”
Thomas Gasser: “Indeed possible that not all GBA variants act via the same mechanism. But by and large, I think that restoring GBA activity early, very early, should be helpful generally.”
Michela Deleidi: “Despite the genetic heterogeneity (that in some cases influences disease severity, see the severe L444P mutation), so far several works conducted in experimental model systems suggest that different mutations affect the same cellular mechanisms likely implicated in GBA-PD pathogenesis.”
Avner Thaler: “I’m not sure we’re in a position to answer this yet, I do believe mild and severe mutations can be grouped but I’m not sure we are yet familiar with all the constraints involved.”
If you had a GBA mutation, which trial, if any, would you enroll in? Or are there any supplements or over the counter medications that you would try (after consulting with your neurologist)?
Michael Schlossmacher: “Participation in well designed, well monitored and well executed trials is the best strategy to glean as much information as possible for our patients and the larger community.”
Mark Cookson: “I’d sign up for as many as I could handle knowing that some will work and some won’t. As for OTC and supplements, I don’t think I would put much hope that these would help with the PD, but if they were useful for feeling better generally (like helping with sleep or other disturbances), then I would certainly discuss with a neurologist.”
Thomas Gasser: “Honestly, I don’t know. Maybe ambroxol, or just wait until something more convincing comes along. Should not be too far away.”
Avner Thaler: “I wouldn’t enroll in current studies but I’m biased as a caretaker and clinician. I would defiantly try ambroxol, but regarding targeted therapies, I would wait the first trials out. I think the tougher question regards the non-manifesting heterozygote carriers of severe mutations. I think in their case I would enroll to whatever trials come on the market.”
2. MA Woeste, D Wachten (2017), "The Enigmatic Role of GBA2 in Controlling Locomotor Function", Frontiers in Molecular Neuroscience, page 386 (doi: 10.3389/fnmol.2017.00386).
3. L Straniero, V Rimoldi, Maura Samarani, S Goldwurm, A Di Fonzo, R Krüger, M Deleidi, M Aureli, G Soldà, S Duga, R Asselta (2017), "The GBAP1 pseudogene acts as a ceRNA for the glucocerebrosidase gene GBA by sponging miR-22-3p", Scientific Reports, volume 7, article number 12702 (doi: 10.1038/s41598-017-12973-5).
6. J Magalhaes, ME Gegg, A Migdalska‐Richards, AHV Schapira (2018), "Effects of ambroxol on the autophagy‐lysosome pathway and mitochondria in primary cortical neurons", Scientific Reports, volume 8, article number 1385 (doi: 10.1038/s41598-018-19479-8).