Alpha-synuclein gene silencing effective for treating neurodegenerative disorders: Research

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, and collaborators at The Parkinson's Institute and the Mayo Clinic have published new research findings in the journal Public Library of Science (PLoS). The new data show effective silencing of the alpha-synuclein gene with an RNAi therapeutic administered directly to the substantia nigra in the CNS of non-human primates. Alpha-synuclein is widely believed to play a central role in the development of Parkinson's disease, where the accumulation of excess alpha-synuclein protein in the substantia nigra has been associated with the cause and/or progression of the disease.

“a major scientific breakthrough that happens once every decade or so”

"These new findings add to a growing body of data on the applications of RNAi therapeutics for the treatment of neurodegenerative disorders, such as Parkinson's disease. Indeed, direct delivery of RNAi therapeutics in the CNS represents an important component of our overall product development strategy," said David Bumcrot, Ph.D., Director, Research at Alnylam. "We remain committed to advancing this promising therapeutic modality to patients."

Parkinson's disease is a chronic, degenerative neurological disorder that affects dopaminergic neurons in the brain involved in the control of movement. Symptoms include tremor, slowed movement, and rigid muscles. Recent research indicates that at least one million people in the United States, and more than five million worldwide, suffer from Parkinson's disease. There exists a significant need for disease modifying therapies for the treatment of Parkinson's disease as no such treatments are currently available.

"A wide range of genetic, epidemiologic, and laboratory data support the hypothesis that reducing levels of alpha-synuclein in the brain may slow or even halt the progression of Parkinson's disease and its associated symptoms," said Donato A. Di Monte, M.D., Professor & Senior Research Group Leader at the German Center for Neurodegenerative Diseases (DZNE) in Bonn, and previously with The Parkinson's Institute. "Accordingly, we are encouraged by these important results, which for the first time demonstrate RNAi-mediated silencing of alpha-synuclein in the substantia nigra of non-human primates. To date, no drugs have been identified that are capable of lowering alpha-synuclein levels, and these data certainly support further development of an RNAi-based approach for the treatment of Parkinson's disease."

The published data (McCormack et al., PloS ONE, 5: e12122, 2010) demonstrated that direct delivery of chemically modified siRNAs specific for alpha-synuclein resulted in significant silencing of the target gene in the substantia nigra in the non-human primate brain. A significant 40-50% suppression of both alpha-synuclein mRNA and protein levels was observed in treated animals, as compared to controls. In these preliminary studies, the siRNA was found to be well tolerated after direct CNS administration; no complications or adverse events were observed, including the absence of detectable microglial activation or change in the number of nigral dopaminergic neurons. These results suggest that RNAi therapeutics may be useful in reducing the pathogenic burden of alpha-synuclein in patients with Parkinson's disease.