2018 has been particularly rich for scientists working on Parkinson’s disease. Whether in the field of fundamental research (to gain new knowledge about the causes and mechanisms of the disease), or in clinical research (directly with patients), this year has brought a lot of hope for the Parkinson’s community. Let’s look briefly at the 3 major areas of discovery:
A brief look at the progress of Parkinson’s research in 2018
New therapeutic avenues to manage the symptoms of the disease
Improvement of traditional medicines
Since the 1960s, levodopa has been the standard treatment for Parkinson’s disease. Unfortunately, its incredible efficiency is accompanied by motor fluctuations and dyskinesias induced after several years of use. These side effects are closely related to the short life of this molecule in our body and its erratic intestinal absorption.
A lot of researches is therefore aimed at prolonging the duration of efficacy of the product and / or favoring non-oral modes of administration. Thus, many new drugs use the traditional combination levodopa / carbidopa but in other formulations that allow them to attain longer action times and therefore less fluctuation effects. Other options are also evaluated, including prodrugs that are assimilated more regularly in the digestive system or new capsules containing levodopa in a folded structure such as an accordion that releases the product in a much more controlled manner.
In regards to new delivery devices, trials are currently being conducted to evaluate the efficacy and safety of infusion of a new intrajejunal levodopa / carbidopa gel to treat motor fluctuations. Other research in advanced stages of development involves the administration of levodopa subcutaneously or intra-pulmonally. Some of these drugs are in the final stages of testing and are expected to be available in the Canadian market in the coming years.
After more than 50 years of clinical use as a standard treatment for Parkinson’s disease symptoms, levodopa remains a topic of interest and research. But it is not the only one, because dopamine, or its lack in Parkinson’s disease, is only part of the equation. Of all the neurotransmitters that control our activity, some modulate the action of dopamine. For example, some new drugs will activate the glutamate pathway, an excitatory neurotransmitter, that regulates dopaminergic pathway activity and thus, improve the availability of dopamine and reduce episodes of dyskinesia. These molecules work in combination with levodopa, or other dopamine agonist agents, to improve the quality of life of patients.
Closer to us in time, two new products aimed at reducing the number of off-periods in patients further along in the disease will soon be available in Canada (Movapro®, as a subcutaneous injection and KynMobi® as a film).
But the research does not stop with the management of motor symptoms. For several years, the voices of patients and their caregivers have largely changed the research focus of managing motor symptoms towards the overall improvement of quality of life and treatment of non-motor symptoms.
Thus, many clinical trials, often designed in collaboration with patients, are in progress. The most promising are in the areas of cognitive impairment, anxiety, psychological disorders and constipation.
Use of stem cells
For many years, stem cell research has brought hope to the Parkinson’s community. Its principle, apparently simple, is to replace dead dopaminergic neurons in patients with brand new neurons derived from stem cells (undifferentiated cells that have the potential to become any type of cell, liver, kidney or neuron, for example).
Unfortunately, the ethical issues related to the use of embryo cells and the lack of dopaminergic activity of transplanted cells have slowed research in this area in the last 5 years.
Today, the scientific community has managed to overcome this moral challenge by using skin cells or blood cells instead of embryonic cells, then transforming them into stem cells and ultimately into dopaminergic neurons.
On the other hand, researchers have clearly improved the culture methods of these neurons so that once transplanted, they retain their dopaminergic activity at a therapeutic level and do not become stem cells again.
Researchers have accumulated incredible experience in this field that is now opening up to research in humans. It is this type of innovative therapy that made headlines in a Phase I trial in Japan (a safety trial with a very limited number of unaffected individuals).
This type of research not only has the potential to modify the progression of the disease but also to be used for personalized medicine. A patient’s skin cells could be transformed into dopaminergic neurons to directly evaluate the efficacy of new therapeutic molecules in the laboratory.
Use of gene therapy
This option involves asking the cells in our body to produce active molecules to fight the disease, rather than administering them to patients.
Through viruses and other molecular technologies, new genetic material is inserted into the information already contained in the nucleus of our cells. Thus, neurons could produce more dopamine or decrease the production of alpha-synuclein, a protein whose aggregation is responsible for the death of neurons.
One of the major advantages of this option is its very limited activity from a physiological point of view. Not only is the cell-produced molecule produced locally, but unlike the drugs it delivers, it does not spread throughout the body causing side effects.
New therapeutic avenues to slow or stop the progression of the disease
Reusing of repurposed drugs for other diseases
These products are already available on the Canadian market, but they are approved for other diseases (eg cancer, diabetes). However, their mechanism of action suggests efficacy on the symptoms or progression of Parkinson’s disease. However, we do not have data on the actual efficacy of these products or their safety in people living with Parkinson’s disease who should be exposed to these products over the long term. Studies must therefore be conducted. The advantage is that all toxicity studies on animals have already been done. This brings these drugs closer to being on the market.
There are more than 8 drugs in Phase II and one major trial in Phase III. These drugs are mainly derived from research in cancerology and diabetology because they interact with the dopaminergic pathway that is deficient in Parkinson’s.
Although available in the Canadian market, the use of these products is not recommended as there is not yet enough data to demonstrate their efficacy and safety in patients living with Parkinson’s disease.
Specific targeting of alpha-synuclein protein
Alpha-synuclein is a protein that is normally found in brain neurons. The normal function of this protein is still unknown. However, we know that it participates in the death of neurons, including taking an abnormal form, and then aggregating into small clusters, Lewy bodies. The neurons are then unable to eliminate this cellular waste, which ends up killing the cell.
The new therapies have several targets: 1) reducing the production of this protein 2) the preventing of its withdrawal into its abnormal form 3) and finally the facilitating of its elimination.
Two types of treatment are being evaluated in clinical trials: Injection of immunoglobulins (antibodies made in the laboratory or by animals) that will directly “attack” the protein aggregates. In this case, we are talking about passive immunization because our immune system is not directly involved.
On the other hand, a vaccine is being tested to assess whether our own immune system is capable of producing antibodies that will “fight” against the clumps of alpha-synuclein and make them disappear. In this case, it is active immunity.
Targeting genes GBA & LRRK2
The GBA and LRRK2 genes are responsible for nearly 10% of Parkinson’s disease cases. Many studies aim to understand how the activation of these genes is responsible for the disease in families.
The genetic study of Parkinson’s disease is crucial because even though the number of Parkinson’s cases entirely attributable to genetics is relatively small, these studies allow us to better understand the genetic and molecular mechanisms underlying the disease, even its idiopathic form (of which we do not know the causes). Once these mechanisms are better understood, researchers will then have the opportunity to work on targeted and early interventions to stop the development of the disease.
Best methods for diagnosing and monitoring the evolution of the disease
Early diagnosis of the disease
Today, the diagnosis of Parkinson’s disease is essentially clinical. It is based on the assessment of motor symptoms by the neurologist. Unfortunately, this diagnosis is delivered when the disease has already progressed and more than 50% of the dopaminergic neurons have died.
There is significant interest in developing new technologies that will enable the diagnosis of disease at earlier stages using biomarkers (objective results from laboratory analysis or imaging). Indeed, the earlier we will be able to diagnose the disease, the more we will be able to develop new therapeutic approaches to treat the disease. It is likely that these early interventions can stop the progression of the disease before the damage caused become too important and irreversible.
There is a wealth of research-based studies of combinations of non-motor symptoms that could be used to diagnose the disease early. For example, the correlation between restless dreams and loss of smell is an early predictor of the disease. Non-invasive tests such as facial symmetry assessment also showed a strong predictive power.
On the other hand, other technologies are being studied to better define Parkinson’s disease, including magnetic resonance, the detection of alpha-synuclein in biopsies of skin or the intestinal mucosa or analysis of the retina in the eye.
Monitoring the evolution of the disease
Telemedicine and virtual therapies are becoming indispensable allies for healthcare professionals. Imagine sensors in your smartphone or directly in your clothes that record your motor symptoms and provide them to your doctor who can then adjust your medication.
In an increasingly overburdened health system, these technologies can be very effective in improving access to care. For example, a research team has developed a behavioral therapy to treat depressive episodes in people living with Parkinson’s disease. This type of virtual therapy offers a great potential for people for whom mobility becomes problematic in a territory as big as Quebec.
All these avenues of research are extremely promising and give us a better understanding of the disease, its causes, its mechanism of evolution. They offer us new avenues of treating the symptoms while tracking its progression.