Alnylam and partners silence gene implicated in Parkinson’s disease

New research published in journal PLoS shows silencing of alpha-synuclein in the substantia nigra of non-human primates with an RNAi therapeutic

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CAMBRIDGE, Mass.—Evidence that Alnylam Pharmaceuticals Inc. continues to make progress in breakthrough RNAi therapeutics has emerged from work published by the company and its collaborators at the Parkinson's Institute and the Mayo Clinic.
The new research findings, which appeared in the journal Public Library of Science (PLoS), show effective silencing of the alpha-synuclein gene with an RNAi therapeutic administered directly to the substantia nigra in the central nervous system (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.

The published data demonstrate 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 to 50 percent 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, both of which are indicators of inflammation and general neurotoxicity that are important to investigate for any novel therapeutic. The results suggest that RNAi therapeutics may be useful in reducing the pathogenic burden of alpha-synuclein in patients with Parkinson's disease.

The probable mechanism of action is explained by Dr. David Bumcrot, director, research at Alnylam: "The siRNA unwinds and is incorporated into the RISC complex, where it is then directed towards the targeted messenger RNA (mRNA) that is known to be involved in the disease pathway. The specific mRNA gets degraded—or silenced—thereby preventing the disease-causing proteins from being made," Bumcrot says.

"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," says Dr. Donato A. Di Monte, professor and 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. 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."

"These new findings add to a growing body of data on the applications of RNAi therapeutics for the treatment of neurodegenerative disorders," adds Bumcrot. "Indeed, direct delivery of RNAi therapeutics in the CNS represents an important component of our overall product development strategy. We remain committed to advancing this promising therapeutic modality to patients."

Alnylam has a broad pipeline of RNAi therapeutics currently in clinical and preclinical development for the treatment of a wide range of disease areas, Bumcrot notes, including respiratory syncytial virus (RSV), liver cancers, transthyretin-mediated amyloidosis and hypercholesterolemia. In addition, similar to its efforts in Parkinson's disease, Alnylam is currently developing a treatment for Huntington's disease. This program, known as ALN-HTT, is now in preclinical development and is being developed in collaboration with Medtronic.

The Alnylam-Mayo Clinic-Parkinson's Institute study was funded by a Linked Efforts to Accelerate Parkinson's Solutions (LEAPS) award from the Michael J. Fox Foundation for Parkinson's Research. Alnylam has an agreement with the Mayo Clinic whereby Mayo has granted Alnylam an exclusive license to certain patents and know-how related to alpha-synuclein.

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