Bottom line takeaway: In 1997, researchers learned that the protein alpha-synuclein and the gene that encodes the protein play a role in Parkinson's disease. Since then, alpha-synuclein has been the focus of intensive efforts by researchers working to definitively characterize its role in PD and its potential as a target for neuroprotective therapies. The Michael J. Fox Foundation is helping to lead these efforts, and awardees are engaged in a range of promising projects to develop therapies against alpha-synuclein.
The potential for patients: Alpha-synuclein is a protein whose function in the healthy brain is not currently known, but which is of great interest to Parkinson's researchers: Clumps of alpha-synuclein exist in the cells in all people with PD. Researchers hypothesize that preventing or clearing out these clumps may prevent, slow or halt disease progression. Since alpha-synuclein may play a role in the development of both genetic and idiopathic cases of Parkinson's, a therapy against this target could help all those living with PD.
The challenge for researchers: While they know what they want to do, researchers don’t yet know how to do it. How can they stop the alpha-synuclein from clumping? They’re trying a variety of approaches such as immunotherapy — using introduced or induced antibodies to attack the protein clumps — and drug compounds that may bind to alpha-synuclein or its related pathology (such as enzymes) and prevent toxicity.
The MJFF approach: The Foundation is supporting research in various stages of development. Pre-clinical studies are looking at antibodies and vaccine approaches. Some established drug compounds are in laboratory testing, and other projects are aimed at identifying compounds that can work against alpha-synuclein and related targets. The AFFiRiS Phase I clinical trial is testing a vaccine immunotherapy approach against alpha-synuclein, and results are expected in Q2 2014.
Reasons for optimism: Industry has taken interest in alpha-synuclein as a viable target. In 2013 biotech company Biogen Idec signed on to MJFF-funded projects from two smaller companies: Amicus Therapeutics is testing compounds to heighten GCase enzyme activity, which may keep alpha-synuclein in check, and Proteostasis is testing therapeutic candidates to inhibit the Usp14 enzyme, a strategy that has shown to prevent alpha-synuclein clumping in pre-clinical models. Biogen Idec’s support of these studies is a success of the MJFF de-risking model, which elevates promising early-stage research to the attention of larger funders and closer to the clinic.
MJFF research partners: The Foundation is supporting academic and industry partners around the world to speed research against this target toward clinical application for patients.
Notable quotes: “By affecting alpha-synuclein using antibodies, we may be able to slow the disease, preventing it from spreading to the nervous system. We are currently unable to offer treatment affecting disease progression, but treatment with antibodies may prove to have this potential,” says Kim Andersen, head of pharmaceutical company Lundbeck’s research in Denmark.
“We look forward to advancing our disease-modifying approach to develop therapeutic candidates that can address several protein aggregation disorders, including Parkinson’s and Alzheimer’s disease,” says Markus Haeberlein, MSc, PhD, senior vice president and head of research at Proteostasis Therapeutics.
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