Neurons cannot divide which means that if they degenerate, they cannot be replaced. This inability to regenerate neurons is a primary challenge in addressing neurodegenerative diseases. Parkinson’s disease is characterized both by the loss of dopaminergic neurons and the presence of protein aggregates. These aggregates are toxic and spread the pathology to neighboring cells, thereby contributing to the progression of the disease. Despite being known for over a century, Parkinson’s disease still has no treatment to stop or slow down the pathology. The actual treatments for Parkinson's disease remain largely symptomatic. Consequently, numerous research teams are striving to develop therapies that can slow down or halt the disease progression, with many promising avenues being explored.

Immunotherapy emerges as a promising treatment option for the early stages of the disease. Our laboratory has developed a derived monoclonal antibody, such as a mini antibody, to specifically target phosphorylated alpha-synuclein (aSyn), the protein that is aggregating in PD. The antibody contains only the fragments that bind to the antigen, thus making it small and easier to deliver into neurons. Our research indicates that these mini antibodies effectively bind to phosphorylated aSyn and limit the aggregation of the protein. However, it is important to note that this strategy is primarily effective during the early stages of the disease.

In advanced stages of Parkinson's disease, there are fewer dopaminergic neurons remaining to target with immunotherapy. Consequently, cell replacement therapy becomes an attractive option to restore dopaminergic innervation. Previous clinical trials involved grafting fetal cells, but the use of fetal cells raises ethical concerns and poses challenges due to impurities in the cell mixture. To address these concerns, ongoing clinical trials are exploring the use of induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs).

Despite advancements in cell replacement therapy, challenges persist. The pathology in the brain persists, affecting also newly grafted neurons, while surrounding cells may also be vulnerable to degeneration due to the existing pathology. To address this issue, our team has developed a cell line capable of producing antibodies targeting pathological alpha-synuclein. These antibodies are secreted outside the cells and thus have the potential to not only impact the transplanted neurons but also influence surrounding cells affected by the pathology. To control the production of our antibodies, we use an inducible system based on the TeT-ON system. This system allows the expression of the derived antibody only in the presence of tetracycline or one of its analogues, such as doxycycline in our case.

In our study, we aimed to recreate synucleinopathy, a characteristic pathology of diseases like Parkinson's, in rodents. To do this, we injected a combination of aSyn preformed fibrils and a viral vector expressing aSyn into the rodents' midbrain. This induced a condition similar to what is observed in humans, where there is a spread of α-synuclein pathology and a loss of dopaminergic neurons.

After a month, we then grafted cells that express the antibodies to evaluate its efficiency in protecting grafted cells from the existing pathology. Doxycycline was administered to the rodents in the drinking water, to induce antibody production. Our experimental model allows us to mimic the challenges faced when transplanting cells into a diseased brain environment, reflecting the real-life struggles encountered in treating conditions like Parkinson's disease.

Initial results from our study are promising. We observed a reduction in pathological protein aggregates within the transplanted cells, indicating that the antibodies produced by these cells may indeed offer protection against synuclein pathology. These results are encouraging and suggest that further research into the effectiveness of these antibodies in protecting surrounding cells is needed. If successful, this approach could represent a valuable long-term therapeutic strategy for people living with Parkinson’s disease.

Overall, we trust that our neuroregenerative approach has the potential to significantly advance cell replacement therapies for individuals living with Parkinson's disease.

Béatrice Morin, MSc is a student at the CERVO Brain research centre, Université Laval, in Québec, Canada. She was an abstract presenter at the WPC 2023 in Barcelona.

Ideas and opinions expressed in this post reflect that of the author solely. They do not reflect the opinions or positions of the World Parkinson Coalition®