Gene Silencing Neuroprotective Treatment Developed for Parkinson's Disease

A gene silencing therapeutic agent is under development to treat Parkinson's disease (PD) by reducing expression of the protein alpha-synuclein.

A team of researchers led by Matt Farrer, Ph.D., from the Mayo Clinic Jacksonville (FL, USA), with collaborators at Alnylam Pharmaceuticals (Cambridge, MA, USA) and the Parkinson's Institute and Clinical Center (Sunnyvale, CA, USA; www.thepi.org), will work to optimize a small interfering RNA (siRNA)-based therapeutic agent 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 conventional small-molecule therapeutics.

The work is being funded under the Foundation's LEAPS (Linked Efforts to Accelerate Parkinson's Solutions) 2007 initiative. The Michael J. Fox Foundation (MJFF; New York, NY, USA) has committed up to US$3.8 million for the development of treatment for Parkinson's disease. "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.”

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 significant feature of non-inherited PD as well. Continued studies will analyze whether reducing the levels of alpha-synuclein in the brains of individuals with PD 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 a previous study, researchers have shown that targeted siRNAs reduce alpha-synuclein levels in mouse models of PD. 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 effective, 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.


Related Links:
Mayo Clinic
Alnylam Pharmaceuticals