Researchers reduce production of alpha-synuclein in the brain - offers hope for Parkinson's disease

Mayo Clinic researchers have developed a method to reduce the production of alpha-synuclein in the brain.

Alpha-synuclein is a protein that is believed to be central to the cause of Parkinson's disease. All patients with Parkinson's disease have abnormal accumulations of alpha-synuclein protein in the brain.

Additional audio and video resources, including excerpts from an interview with Dr. Maraganore describing the research, are available on the Mayo Clinic News Blog.

The new method involves the delivery of RNA interference compounds directly to selected areas of the brain via injection. The RNA interference compounds silence the gene that produces alpha-synuclein, according to the Mayo researchers. The study was published this month in Molecular Neurodegeneration.

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 1 million people in the U.S. are believed to have Parkinson's disease, and 2 percent 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," says Demetrius Maraganore, M.D., a Mayo Clinic neurologist.

Previous studies 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 invented a method to treat Parkinson's disease by reducing alpha-synuclein expression. Mayo Clinic patented and licensed their invention to Alnylam Pharmaceuticals, Inc. 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," says 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," says Dr. Farrer. "We are hopeful, as preliminary studies suggest this is possible."

"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," says Dr. Maraganore. "We envision that the therapy would be delivered through 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."

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.

Other members of the Mayo Clinic research team included Jada Lewis, Ph.D.; Andrew Hope, Ph.D.; Cynthia Zehr, Ph.D.; Sarah Lincoln; Adam Braithwaite; Zhen He, Ph.D.; Sina Ogholikhan; Kelly Hinkle; Caroline Kent; Michael Heckman and Julia Crook, Ph.D. Contributors from Alnylam Pharmaceuticals, Inc. included David Bumcrot, Ph.D.; Ivanka Toudjarska; Klaus Charisse; Ravi Braich and Rajendra Pandey.

This study was funded in part by a grant from the Michael J. Fox Foundation. Mayo Clinic has an agreement with Alnylam whereby Mayo has granted Alnylam an exclusive license to certain patents and know-how. Mayo Clinic and inventors of this intellectual property may receive developmental milestone and/or royalty payments pursuant to this agreement.