Antibodies that selectively target the misfolded form of the alpha-synuclein protein — that which underlies the development of Parkinson’s disease — reduced the formation of alpha-synuclein clumps and improved dopamine levels in a mouse model.
The study with that finding also provided a framework for screening antibodies (immunotherapies) that target alpha-synuclein to identify those with the best therapeutic properties.
The study, “Characterization of novel conformation-selective α-synuclein antibodies as potential immunotherapeutic agents for Parkinson’s disease,” was published in the journal Neurobiology of Disease.
Nerve cell damage in Parkinson’s disease is caused by the build-up of toxic forms of the protein alpha-synuclein that forms clumps of misfolded proteins known as Lewy bodies.
Studies have found that reducing misfolded alpha-synuclein may be an effective therapeutic strategy for treating the disease.
One idea is to create antibodies that specifically target misfolded alpha-synuclein, avoiding the problems associated with reducing the levels of properly folded, fully functioning alpha-synuclein.
This was the approach taken by a group of researchers at the University of Pennsylvania in Philadelphia. Their first step was to create and isolate antibodies that were highly selective for misfolded alpha-synuclein, then test the best candidate in a Parkinson’s mouse model to find out if the antibody had therapeutic potential.
To create these antibodies, mice were injected with misfolded alpha-synuclein and the antibodies generated during the immune response were isolated and screened to find the best candidate.
Brain sections from Parkinson’s patients with high numbers of Lewy bodies first were used to identify antibodies that selected pathological (disease-associated) alpha-synuclein.
The team hoped these antibodies may be used in humans, so those that bound to both mouse and human alpha-synuclein were preferred.
Further testing found antibodies that bound to only the misfolded form of alpha-synuclein, but not the normal form.
The final screen was to identify a candidate that prevented the development of alpha-synuclein pathology in neurons. Mouse neurons were treated with the previously selected antibodies and were exposed to toxic forms of human alpha-synuclein protein. The highest performing antibody, named Syn9048, reduced pathology [disease manifestation] by 97%.
As antibody treatments for Parkinson’s are likely to be given after symptoms emerge (when brain disease is already established), a mouse model was chosen to test the effectiveness of Syn9048 to reduce disease and rescue nerve cell function.
Mice were injected with misfolded alpha-synuclein, which triggered nerve cell loss in the same areas of the brain as seen in Parkinson’s patients. Then they were given Syn9048 or a control antibody every week for six months.
All mice gained weight in a similar manner, showing that the therapy was well-tolerated.
Examination of the mouse brains showed that Syn9048 reduced the aggregation of alpha-synuclein in areas related to Parkinson’s disease.
Although Syn9048 was not successful in rescuing cells responsible for producing dopamine (dopaminergic), it increased dopamine levels in the brain, which suggested that the reduction of alpha-synuclein pathology may improve the function of remaining dopamine-producing neurons.
“Our study suggests that immunotherapy will not likely reverse existing pathology, but may halt the spread of pathology through the brain, preventing further motor and cognitive decline,” the researchers wrote.
“Future studies assessing brain-wide spread patterns could help predict the maximal possible benefit of immunotherapy and could be used to determine when during disease progression immunotherapy would need to be administered to be most efficacious,” they added.