Why I Am Excited and Optimistic About the Prospects of Finding Neuroprotective Therapies in Parkinson's Disease

Parkinson’s disease (PD) is a chronic neurodegenerative disease that affects 7-10 million people worldwide. While the cause of the disease remains unknown, tremendous progress has been made in developing therapeutic options for management of PD motor disability. The major area of unmet need remains finding therapeutics to slow or halt disease progression and ultimately to reverse its cause. Such therapies are called: “disease modifying” or “neuroprotective”.

Terminology you should become familiar with:

Neuroprotective: Neuroprotection means that the therapy is able to reduce cell death or salvage damaged neurons. We are able to reliably measure neuroprotective effect in animal models and in cell cultures. In order to make such determination in PD patients, we need to have reliable ways to measure cell counts or cell function in a living person, which remains a challenge. For that reason, clinical trials usually measure ability of the intervention to slow disease progression based on a clinical scale or other clinically relevant outcome measures. For that reason “disease modification“ is the preferred terminology for clinical trials. It is the hope that disease modifying intervention does truly impact and slow the process of neurodegeneration.

Biomarkers: Biomarker is a “measurable indicator of some biological state or condition” (Webster dictionary). The key is that it is objective, reliable and reproducible. A perfect example of a biomarker is blood sugar level as an indicator of diabetes or cholesterol level as a risk factor of cardiovascular disease. Biomarkers are essential for screening of the population at risk (disease trait) or for monitoring disease progression (disease state). One of the areas of major unmet needs in Parkinson’s is lack of such objective biomarkers.

History of disease modifying trials in PD: There has been a tremendous effort to develop disease modifying interventions in PD. Over the last three decades multiple drugs have been tested in different phases of clinical trials and none have been successful. What are the reasons for failure? As outlined in Dr Stoessl’s blog dated June 18, 2018, there are multiple factors. We still do not know the cause of PD. Our animal models that are used for drug screening are not reflective of humans’ Parkinson’s disease, we lack biomarkers of PD progression, and we might be using not sensitive enough outcome measures, to name a few …

So now that I have outlined all the challenges, why do I remain optimistic (aside from being an eternal optimist)? I believe that the discoveries of the last decade better our understanding of the mechanisms underlying the disease: PD genetics, ways to screen out less than promising therapeutics, all bring us to the next level of drug discovery. Below are a few examples of most promising therapeutic targets:

α-synuclein targeting therapies: α-synuclein is a protein that accumulates in the cells of people with PD. α- synuclein is a normal constituent of cells, but in the disease state there is pathological aggregation of the protein, failure to clear it effectively from the cells, and potentially propagation from cell to cell. All these changes lead to cell dysfunction believed to be essential in the mechanism of PD development. For these reasons there is tremendous effort in development of α–synuclein targeting therapies. There are a number of different α–synuclein targeting approaches in various phases of development. These include ways to reduce α–synuclein production, intracellular aggregation, increase intracellular and extracellular protein degradation and reduce extracellular propagation. Of these, α–synuclein targeting immunotherapies are most advanced in the clinical trials. The target of these therapies is reduction of extracellular α–synuclein by way of either active vaccination (ClinicalTrials.gov Identifier: NCT02267434) or passive immunization by intravenous administration of antibodies. Two companies are currently testing the latter approach in early phase clinical trials (Roche, ClinicalTrials.gov Identifier: NCT03100149) and Biogen (ClinicalTrials.gov Identifier: NCT03318523). Both agents had extensive preclinical testing and an acceptable safety profile in Phase I studies. While we have to be cautious regarding promises of success, especially with failures of similar approaches in Alzheimer’s disease, these are exciting therapeutic targets tackling underlying disease biology.

Therapeutics aimed at specific PD subtypes: We are well aware that the clinical course of PD can vary substantially among different patients even with a similar age of onset and disease duration. There is a tremendous effort to better understand the biological underpinnings of PD heterogeneity. One obvious target is the subset of people with PD (PwPD) who carry a specific PD related genetic mutations. While a minority of PwPD carries a single PD relevant genetic mutation, these can teach us a lot about PD mechanisms at large. GBA and LRRK2 are two most relevant mutations with therapeutics already in clinical trials.

GBA targeting therapeutics: Glucocerebrosidase is an enzyme essential for normal function of the part of the cell called lysosomes that are responsible for the clearance of proteins and thus assuring normal cell function. The function of the enzyme is coded by the glucocerebrosidase gene (GBA). People who carry two copies of the abnormal gene develop Gaucher disease, the most common lysosomal storage disease.  Interestingly, it was noted that people who carry only one abnormal copy of the gene do not develop Gaucher, but are at higher risk of development of PD. In fact, GBA is not considered the most common genetic risk factor for PD. The relationship between GBA and PD is linked to an inverse relationship between lower levels of glucocerebrosidase enzyme and increased levels of α–synuclein and vice-versa. Due to this relationship, GBA targeting therapeutics are believed to be potentially effective not only in GBA mutation carriers, but also in people with sporadic (no genetic mutation) PD. A number of different therapeutic approaches are in development including ways to increase enzyme production, improve the function of enzyme and reduce the substrate for the enzyme (in a way to reduce the work load for the enzyme). The therapeutic that is most advanced in clinical trials is developed by Sanofi (ClinicalTrials.gov Identifier: NCT02906020) testing substrate reduction approach.

LRRK2 targeting therapeutics: LRRK2 is the most common autosomal dominant mutation associated with PD. While the most common, it is still rare in the general PD population, ranging between 1.5-3% and more common in selected ethnic groups. The role of LRRK2 kinase in PD is still not fully elucidated, but multiple convening lines of evidence indicate that reduction of LRRK2 is associated with neuroprotective effect in PD animal models. A number of companies are working on LRRK2 targeting therapeutics though none of them so far have been tested in PwPD.

In conclusion, the new generation of potential disease modifying therapies in PD are being developed based on the latest scientific discoveries, with much higher vigor in selection of preclinical targets, assuring that the drugs actually reach the brain targets they are supposed to work on and targeting genetic subtypes of the disease. All these are the reasons for my optimism though the challenges still remain. It should be recognized that disease modification is the most challenging treatment target across neurodegenerative disease. In the interim, PwPD should remain active contributors to the drug discovery process including active participation in clinical trials.


Tanya Simuni, MD presented at the Fourth World Parkinson Congress in Portland, Oregon and will be presenting at the Fifth World Parkinson Congress in Kyoto, Japan. She is currently a Professor of Neurology and Director of the Parkinson’s disease and Movement Disorders Center at the Northwestern University Feinberg School of Medicine.

Ideas and opinions expressed in this post reflect that of the author(s) solely. They do not necessarily reflect the opinions of the World Parkinson Coalition®