NEWYORK, NY — The Michael J. Fox Foundation has committed up to $3.8 million for the development of a gene silencing therapeutic to treat Parkinson’s disease by reducing expression of the protein alpha-synuclein. A team of researchers led by Matt Farrer, PhD, of Mayo Clinic Jacksonville (Florida) with collaborators at Alnylam Pharmaceuticals and The Parkinson’s Institute and Clinical Center will work to optimize a small interfering RNA (siRNA)-based therapeutic that could slow or stop the progression of Parkinson’s disease. If successful, the project could result in an entirely new class of drug targeting the alpha-synuclein gene, which has proved difficult to modulate using traditional small-molecule therapeutics.
The work is being funded under the Foundation’s LEAPS (Linked Efforts to Accelerate Parkinson’s Solutions) 2007 initiative. LEAPS 2007 was funded with a lead gift from the Edmond J. Safra Philanthropic Foundation. The Edmond J. Safra Philanthropic Foundation has been one of the most steadfast supporters of The Michael J. Fox Foundation since its inception.
“Available Parkinson’s treatments mask symptoms but do nothing to halt or slow underlying disease progression,” said Katie Hood, chief executive officer of MJFF. “More and more scientific evidence supports the hypothesis that lowering alpha-synuclein levels in the brain could achieve the so-called ‘Holy Grail’ of PD research, a neuroprotective therapy. But no drugs have been identified to date that are capable of reducing alpha-synuclein expression; new approaches are needed. This LEAPS grant is characteristic of how The Michael J. Fox Foundation goes about its work — making big bets on fresh ideas with potential to impact patients’ quality of life.”
While its normal function in the brain remains unknown, the accumulation of excess alpha-synuclein has been shown to be the cause of some familial forms of PD. Clinical, genetic and experimental evidence exists to show that alpha-synuclein accumulation in neurons may be a key feature of non-inherited PD as well. Continued research will analyze whether reducing the levels of alpha-synuclein in the brains of people with Parkinson’s can slow the progression of the disease.
RNA interference (RNAi) is a natural mechanism present in all cells whereby small RNA molecules (the siRNAs) specifically silence gene expression by the targeted destruction of messenger RNA, the molecule that contains the instructions for protein synthesis.
In previous work funded under The Michael J. Fox Foundation’s Target Validation initiative, the LEAPS researchers have demonstrated that targeted siRNAs reduce alpha-synuclein levels in mouse models of Parkinson’s disease. They will now push this work forward by identifying the optimal alpha-synuclein siRNA drug candidate, then establishing efficacy and the “therapeutic window” for brain infusion in animal models. If successful, this project could ultimately lead to the development of an alpha-synuclein siRNA candidate drug that, in the future, could be tested in PD patients in Phase I clinical trials.
LEAPS awards, the signature funding initiative of The Michael J. Fox Foundation, are multi-year, multi-million, multi-disciplinary projects addressing questions with significant practical impact on the treatment of Parkinson’s disease. Continued funding is dependent on completion of predetermined milestones at specific stages.
In addition to coordinating principal investigator Dr. Farrer, professor of neurogenetics, Department of Neuroscience, Mayo Clinic Jacksonville, this LEAPS team includes:
Jada Lewis, PhD, Assistant Professor, Department of Neuroscience, Mayo Clinic Jacksonville — Dr. Lewis will hold primary responsibility for optimizing siRNAs in various mouse models of Parkinson’s disease.
Donato A. DiMonte, MD, Professor, Director of Basic Research, The Parkinson’s Institute and Clinical Center, Sunnyvale, California — Dr. DiMonte, an expert in primate neurology, will hold ultimate responsibility for demonstrating that the candidate siRNAs are neuroprotective in primate models of PD.
David A. Bumcrot, PhD, Director, Research, Alnylam Pharmaceuticals, Cambridge, Massachusetts — Dr. Bumcrot will spearhead the design and synthesis of all candidate siRNAs and lead efforts on investigating siRNA delivery strategies.
While many LEAPS projects involve commercial entities, funds are for stated projects only, dependent upon completion of predetermined milestones at specific stages, and do not represent equity investments. If all milestones are met, this LEAPS allocation will be as follows (rounded figures):
- Mayo Clinic: $1.9 million
- The Parkinson’s Institute: $1.4 million
- Alnylam: $546,000