New Therapy Developed To Halt the Progression of Parkinson's Disease

Alpha-synuclein is a protein that is believed to be essential to the cause of Parkinson's disease.

All patients with Parkinson's disease have abnormal accumulations of alpha-synuclein protein in the brain. The new method involves the delivery of RNA interference compounds directly to selected regions of the brain via injection. The RNA interference compounds silence the gene that produces alpha-synuclein, according to the researchers, from the Florida and Jacksonville centers of the Mayo Clinic.

Parkinson's disease is a progressive disorder that affects nerve cells in the part of the brain that controls muscle movement. Symptoms include tremor, slowed movement, and rigid muscles. At least one million people in the United States are believed to have Parkinson's disease, and 2% of the population can expect to develop the disease during their lifetime.

"While our research has not yet been tested on humans, we expect that these findings will lead to an effective treatment for slowing or even halting the progression of Parkinson's disease,” said Demetrius Maraganore, M.D., a Mayo Clinic neurologist.

Earlier research conducted by Dr. Maraganore and Matthew Farrer, Ph.D., a Mayo Clinic neuroscientist, found that variations in the alpha-synuclein gene result in increased protein production and are sufficient to cause Parkinson's disease in some families, or otherwise increase the risk for Parkinson's disease across populations worldwide.

Drs. Maraganore and Farrer devised a method to treat Parkinson's disease by reducing alpha-synuclein expression. Mayo Clinic patented and licensed their invention to Alnylam Pharmaceuticals, Inc. (Cambridge, MA, USA). Alnylam is leading the effort to commercialize the Mayo invention using Alnylam RNA interference compounds.

"For this study, we developed a lead compound of small interfering RNAs,” commented Heather Melrose, Ph.D., a Mayo Clinic neuroscientist and a lead author of this study. "By infusing this into the brains of mice we were able to effectively reduce the production of alpha-synuclein in the brain. The therapy produced gene silencing that lasted up to three weeks after treatment, and the mice exhibited no ill effects. These are desirable characteristics of a drug therapy ultimately intended to treat disease in humans.”

"Our next step with this research is to test the therapy in mice and primates with experimental forms of Parkinson's disease and prove that we are able to stop the disease progression in those animals,” said Dr. Farrer. "We are hopeful, as preliminary studies suggest this is possible.”

Alpha-synuclein protein also accumulates abnormally in other brain degenerations, including multiple system atrophy (MSA) and dementia with Lewy bodies. Therefore, Mayo researchers expect that RNA interference therapy could be beneficial for patients with those conditions.

"It is important to note that there are significant hurdles to this therapy. The compound needs to be directly delivered to the brain through a neurosurgical procedure--it cannot be given by mouth or injection into a vein,” stated Dr. Maraganore. "We envision that the therapy would be delivered through [U.S.] Food and Drug Administration- [FDA]-approved devices currently used for deep brain stimulation therapy. The deep brain stimulation would treat the existing symptoms of Parkinson's disease, while the administration of the RNA interference compounds might halt the progression of the disease.”

The study was published in the November 2008 issue in the journal Molecular Neurodegeneration.

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Mayo Clinic
Alnylam Pharmaceuticals