Parkinson's disease in 2021: what are the most recent research advances?


Parkinson's disease is characterized by a progressive loss of dopaminergic neurons and a progressive decrease in the concentration of dopamine in the brain. The current treatment for Parkinson's disease is based on the administration of levodopa or dopamine agonists (mimicking the action of dopamine).

While initially effective in improving motor functions, the treatment loses its effectiveness over the long term and leads to the appearance of certain disabling side effects such as dyskinesia and motor fluctuations.


Based on this observation, new therapeutic strategies have been developed to act upstream to prevent the degradation of dopaminergic neurons or, on the contrary, to create new neurons to ensure the production of dopamine.




De nouvelles thérapies pour la maladie de parkinson en 2021
2021: New strategies to treat Parkinson's disease

Immunotherapy: using antibodies to prevent alpha-synuclein accumulation



One of the main mechanisms leading to apoptosis of neurons is the accumulation of a protein called alpha-synuclein. The presence of abnormal aggregates of alpha-synuclein is a strong sign leading to the diagnosis of Parkinson's disease.

It has been shown that this protein can be transferred from one neuron to another, leading to the progressive destruction of all dopaminergic neurons.


The immunotherapy strategy developed consists in limiting the aggregation and propagation of this alpha-synuclein. Antibodies targeting this protein are currently being studied. Two candidates, PRX002 (Prothena) and BIIB054 (Biogen), have demonstrated good tolerance in Phase I trials. Phase II trials on these antibodies are currently underway.


This strategy is an interesting approach, however some points remain uncertain.

In order for the antibodies developed to be effective, they must cross the blood-brain barrier, which protects the brain from circulating blood elements.

Moreover, the use of these antibodies would prevent any action of alpha-synuclein whose main function is not yet understood. Inhibiting the action of this protein could lead to significant side effects that are difficult to predict today.



Use already known molecules


One of the other strategies proposed is to use molecules already on the market and indicated in other pathologies, to block certain mechanisms responsible for the development of Parkinson's disease.


As with antibodies, we can choose to try to reduce the concentration of alpha synuclein.

Other mechanisms can also be targeted such as inflammation of neurons or mitochondrial dysfunction (mitochondria provide the energy necessary for the proper functioning of cells).


Reduce the concentration of alpha-synuclein

Two molecules that reduce the concentration of alpha-synuclein in the brain are currently being studied: nilotinib, which is normally used to treat leukemia, and terazosin, which is used to treat benign prostatic hypertrophy. However, nilotinib appears to have a limited therapeutic effect and terazosin may have side effects that aggravate certain problems associated with Parkinson's disease, such as blood pressure drops.


Restore mitochondrial function

Ursodeoxycholic acid, used in the treatment of primary biliary cirrhosis, has proven its ability to restore mitochondrial function, which is essential for cell survival. Its efficacy has been proven in mouse models and in patients with mutations in the PARKIN and LRKK2 genes (mutations in these genes promote the development of Parkinson's disease).

Following these observations, a Phase II study has been initiated and the recruitment of 30 patients in the early phase of the disease is underway.

N-acetylcysteine and glutathione were also considered as potential candidates, but the Phase II clinical studies did not show any clinical benefit.


Reduce inflammation of neurons

The studies conducted show a strong involvement of the immune system (and thus of inflammation phenomena) in the development and maintenance of Parkinson's disease.

Several molecules are currently being tested to reduce the inflammation of neurons and thus their degradation. The most promising molecule, currently in phase IIa, is AZD3241 which targets myeloperoxidase.

This enzyme plays an important role in immune and inflammatory mechanisms. Inhibiting it would reduce the impact of these mechanisms on the degradation of dopaminergic neurons.


Neurotrophic factors are proteins responsible for the growth and survival of neurons. They are therefore prime candidates for improving the survival of dopaminergic neurons and protecting them from possible disorders.

GDNF (glia-derived neurotrophic factor) is currently being studied. The results are so far mitigated. The first two studies published on this subject showed an improvement in the UPDRS score (a score used to measure all the symptoms related to Parkinson's disease) and a partial restoration of the nigro-striatal pathway (the one most affected in Parkinson's disease).

However, two larger studies subsequently failed to replicate these results.


According to the experts, the development of a treatment based on neurotrophic factors remains an interesting subject of study that must be further explored.



Promising candidate: exenatide

The most promising molecule today is exenatide, normally used for the treatment of type II diabetes. Neuroprotective effects have been observed in preclinical studies in animal models.

A phase II study was conducted and a decrease in the UDPRS score was observed compared to a control group not taking this treatment.

A phase III study on a large number of people is currently underway.

Various mechanisms may explain this potential neuroprotective effect: inhibition of apoptosis ("cell suicide"), reduction of neuroinflammation, reduction of oxidative stress and promotion of neurogenesis (production of new neurons).


The contribution of stem cells: towards the regeneration of neurons


Previously, we've told you about the tremendous potential of stem cells to regenerate lost neurons. The results of Takahashi's study, having begun in late 2018, are expected to be presented soon.

Meanwhile, a single patient study was conducted and published on the New England Journal of Medicine in May 2020.

The objective of this study was to inject dopaminergic neuron progenitor cells into the patient's brain to induce their maturation and to replace the missing cells.



How to obtain this stem cell graft ?

The stem cells used were cells derived from the patient himself and not from an embryo, they are called iPScs (or induced pluripotent cells). They are obtained by taking fibroblasts from the patient through a skin biopsy and then differentiating (transforming) them into this type of stem cells.

These stem cells are then cultured in petri dishes and differentiated into dopaminergic neuron progenitors.


Comment l'effet a-t-il été mesuré ?

Following the transplantation, clinical measurements were performed through two standardized questionnaires widely used in the evaluation of the management of patients with Parkinson's disease :

  • MDS-UDPRS to assess the motor and non-motor symptoms of the patient with Parkinson's disease

  • PDQ-39 to assess the quality of life

In addition, imaging measurements were performed to assess cell survival and variation in dopamine concentration.


Quels ont été les résultats ?

24 months after the transplantation, a total survival of the transplanted cells was observed.

However, the increase in dopamine concentration remained modest.

In terms of the two proposed scores, there was a significant decrease in the PDQ-39 score and a more moderate decrease in the UPDRS score in the off and on phase (a decrease in these scores reflects a better general state of the patient).


Although this study is an interesting first approach, it is not scientifically valid. Only one patient was included and no comparison with a control group was made.

These new therapies based on stem cell transplantation are at the heart of future therapy and will be followed closely in 2021.



Notre conclusion


Research on Parkinson's disease and our increased understanding of neurological mechanisms have led to the development of new therapeutic targets.

The healthcare community is putting all the necessary resources into the development of new therapies.

However, the development of a new therapeutic approach remains extremely complex and time consuming.

Non-drug solutions are also being discussed and developed in the field of medical devices (deep brain stimulation) and rehabilitation (new approaches).


To learn more about the progress of our research around the rehabilitation of Parkinson's disease, click here 👇


References


banner_articles (1).png