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Advances in Parkinson’s Disease research in 2019 at a glance

11 December 2019

The year 2019 was particularly fruitful for researchers studying Parkinson’s Disease. Whether it was basic research (to acquire new knowledge on the causes and mechanisms of the disease), or clinical research (directly with patients), this year brought many avenues of hope for the entire Parkinson’s community.

Why is research on Parkinson’s advancing more slowly than we’d like?

 

Before reviewing the major research advances, it is important to understand why Parkinson’s research progresses so slowly. Here are a few explanations:

Each patient living with Parkinson’s Disease is different. It is therefore difficult to develop a drug that meets everyone’s needs.

Lots of promising clinical research is underway. However, every year, numerous trials find treatments ineffective for several reasons:

    • Parkinson’s Disease is not diagnosed based on a biomarker test (e.g., blood test, imaging). It is a difficult clinical diagnosis. Up to 20% of people enrolled in trials do not have classic Parkinson’s. So these new treatments are not intended for them and the average response in the entire population participating in the study is negative.
    • Parkinson’s Disease could be considered several diseases combined that present different symptoms and causes depending on the individual. Thus, these new drugs may provoke good responses in certain patients while they are ineffective in others. Again, the average response in the population can be negative.
    • Personalized medicine to provide individualized treatments to patients according to their needs seems particularly indicated for the treatment of Parkinson’s. However, perfecting these treatments for small groups of patients is a lengthy process because it is difficult to recruit them for clinical trials (there aren’t many). Furthermore, the pharmaceutical industry often is less incentivized to develop this type of treatment since it views them as unprofitable because they are intended for very small populations.
    • Lastly, Parkinson’s Disease develops slowly, in most cases. Assessing the effectiveness of new treatments therefore takes a long time and requires recruiting many patients for studies. This is why many researchers are trying to find precise, quick and sensitive markers of the development of the disease.

Moreover, researchers have better identified these problems in recent years to accelerate the process of developing new drugs.

New therapeutic avenues to manage the symptoms of the disease

 

In recent years, Parkinson’s research has primarily focused on symptom management. This year was particularly promising in terms of research on drugs that will change the course of the disease.

Specific targeting of the alpha-synuclein protein

 

Alpha-synuclein is a protein that is normally present in the neurons of the brain. The normal function of this protein is still unknown. However, we know that it plays a role in neuron death, particularly by taking an abnormal form, then aggregating into small clusters, Lewy bodies. Neurons are then unable to eliminate this cellular waste that ultimately causes the cell to die.

Accordingly, the new therapies have various targets: 1) reducing production of this protein, 2) preventing its replication in its abnormal form, and 3) lastly, facilitating its elimination.

Two types of treatment are currently in clinical testing: injection of immunoglobulins (antibodies manufactured in laboratory or by animals) that directly attack the protein aggregates. This is passive immunization, because the immune system is not directly involved. Five treatments are in effectiveness and safety testing. They are very promising.

In other avenues, a vaccine is being tested to assess if our own immune system is able to produce antibodies that will fight against alpha-synuclein clusters and cause them to disappear. This is active immunity.

Lastly, three oral drugs are currently being assessed for their ability to eliminate alpha-synuclein aggregates.

Targeting LRRK2 and GBA genes

The GBA and LRRK2 genes are responsible for close to 10% of Parkinson’s Disease cases. Many research projects aim to understand how the activation of these genes produces the disease in entire families.

LRRK2

The pathological activation of the LRRK2 gene increases the risks of developing Parkinson’s Disease. It is the most common mutation in people with Parkinson’s Disease. This gene can be activated in any individual. It is moreover one of the genes activated by pesticides that can induce Parkinson’s Disease.

Once the gene is activated, it codes for the production of a LRKK2 protein. Treatments therefore will aim at reducing the production of this protein or preventing its activity. Two drugs are in advanced research phases. These are drugs that are currently used in oncology, so their development time may be reduced because their safety has already been studied in the past.

GBA

A GBA mutation is found in 5% of people living with Parkinson’s Disease. It is historically the best-known mutation. This mutation results in the overproduction of a toxic substance. Several drugs are currently being tested to reduce the production of this substance. A gene therapy drug is even in development to directly repair the affected gene.

Reuse of drugs available for other diseases

These products are already available on the Canadian market and are approved to treat other diseases (e.g., cancer, diabetes). Moreover, their mechanisms of action suggest effectiveness on the symptoms or progress of Parkinson’s Disease.

These existing drugs present several advantages:

  • Animal toxicity studies have already been conducted. This brings these drugs closer to their marketing for Parkinson’s.
  • Safety studies on healthy volunteers have already been conducted. So we can proceed directly with studies on volunteers with Parkinson’s Disease.

On the other hand, these drugs must be tested correctly on the Parkinson’s population. This can present several challenges:

  • These drugs often were not intended to cross the blood-brain barrier. New dosing methods must therefore be found or the molecule must be modified.
  • These drugs were not intended for an elderly population for which effective and especially safety doses are different. Studies must therefore be repeated to find the appropriate dosage for people living with Parkinson’s Disease.
  • These drugs have often been on the market long enough to become generic. This means that the patent has become public and therefore, that the pharmaceutical industry does not have an interest in conducting new research on these molecules.

More than eight drugs are in Phase II and one major trial is in phase III. These drugs are mainly from cancerology and diabetology research, because they interact with the dopaminergic pathways that are deficient in Parkinson’s.

How long can it take to develop a drug?

 

Before they are made available on the Canadian market, drugs must go through several types of studies to prove their safety and effectiveness.

First, drugs will be tested on animals (toxicological studies), then on healthy volunteers (phase 1 study) to assess safety. Then, drugs are assessed on a limited number of sick people (phase II). These two phases can take between four and six years. If these tests are conclusive, then the drugs are studied on a greater number of individuals and all around the world. These are phase III trials that also take four to six years.

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