The protein alpha-synuclein is believed to play a major role in the development of Parkinson’s disease (PD). Toxic forms of alpha-synuclein can cause neuronal dysfunction and, when secreted from cells, the protein can be taken up by neighboring cells, thereby spreading the disease from one brain region to another. The rationale for this project is that a therapeutic antibody against alpha-synuclein will be able to block its harmful effects, clearing this protein, and thereby preventing the disease from spreading.
Antibodies binding to alpha-synuclein have been selected in cell models. One of them has shown positive effects in pre-clinical models for PD. The selected antibody will be optimized using antibody engineering techniques to increase its ability to bind and remove alpha-synuclein. These studies will also enable us to evaluate the role of the immune system and minimize potential safety issues. Optimized versions of the parent antibody will be tested in models. The most efficacious antibody will be further tested for safety. In order to translate the model studies into the clinic, we will develop assays to evaluate both antibody levels and alpha-synuclein levels in tissues, blood and spinal fluid.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Immunotherapy targeting alpha-synuclein is a new way of treating PD. By neutralizing the toxic forms of the protein the antibody has the potential to delay the progression of the disease and prevent spreading of the disease from one brain region to another. We anticipate that this treatment will delay appearance of symptoms and reduce severity of symptoms. Thereby immunotherapy could be the first disease-modifying treatment for PD.
The studies outlined in the current proposal are designed to generate the most efficacious form of a therapeutic antibody for the treatment of PD. By antibody engineering we will learn about the importance of the strength of antibody binding to alpha-synuclein, and interaction between the antibody and the patient’s immune system. We will also learn about the dynamics between antibody drug levels and target levels. These studies will generate the necessary tools and data required to design a successful clinical trial.
Alpha-synuclein is a sticky protein that clumps in the brains of people with Parkinson's disease (PD). The aim of this study was to test the ability of a therapeutic antibody -- a protein that sticks to alpha-synuclein -- to block alpha-synuclein's harmful effects, remove it from the brain and thereby prevent the spread of PD.
In this study, we first developed an antibody to alpha-synuclein and confirmed its efficacy in alpha-synuclein models of Parkinson's. We then improved this antibody, making it less likely than the original antibody to be destroyed by the immune system. This improvement made the new antibody eligible for human clinical trials. At the same time, we designed several other antibodies to alpha-synuclein as additional therapeutic candidates. These antibodies were designed to be virtually invisible to the immune system, which makes the rejection very unlikely. All the antibodies were tested in vitro and in vivo in models with Parkinson's features. The most promising antibody candidates were selected based on the ease of production and the likelihood of rejection by the immune system. We then created yet another set of antibodies that are easier to produce and tested the production on a small scale. We also established experimental setups for evaluating the antibodies and their targets in clinical trials. The final outcome of the study is a new antibody ready to be tested in clinical trials as a potential therapy for Parkinson's disease.