Research Shows Genetic Evidence that New Therapies Targeting Parkinson's Disease may Cause Harm


SAN DIEGO — NorthShore University HealthSystem (NorthShore) and Mayo Clinic researchers have partnered on a study that shows genetic and clinical evidence that therapies targeting the expression of alpha-synuclein — a gene whose function is involved in the development and progression of Parkinson's disease — may accelerate disease progression and increase the risk of physical incapacitation and dementia. If replicated, the findings will have profound implications for therapies under development for Parkinson's disease.

"Our research suggests therapies that seek to suppress alpha-synuclein in Parkinson's disease may actually accelerate the disease process and increase the risk for developing severe physical disability and dementia,"..."We believe it is our responsibility to release these data because this type of treatment may have long-term harmful effects."

Alpha-synuclein ...Since its discovery as a cause of familial Parkinson's disease nearly 20 years ago, alpha-synuclein has been the focus of intensive efforts by researchers working to definitively characterize the protein's role in idiopathic Parkinson's disease and its potential as a target for neuroprotective therapies. It has also been the focus of multiple efforts to develop a molecule that suppresses the protein function. A vaccine that targets alpha-synuclein (reducing alpha-synuclein levels) is currently in Phase I clinical trials, and a number of molecules that target the protein for reduction are in advanced stages of preclinical development.

"For the first time we observed that while over-expression of alpha-synuclein increases the risk for developing Parkinson's disease, conversely, under-expression is associated with worse motor and cognitive outcomes after the disease starts," says first author Katerina Markopoulou, M.D., Ph.D., a neurologist at NorthShore. "This raises concerns about the efficacy and safety of therapies designed to reduce alpha-synuclein expression in Parkinson's disease."...

The scientists found that patients who had the reduced expression genotype had a 23 percent greater risk of becoming wheelchair-dependent or developing dementia.

"This is the first large genetic association study of alpha-synuclein and longitudinal outcomes in Parkinson's disease," says Eric Ahlskog, M.D., Ph.D., a Mayo Clinic neurologist and author on the study. "If replicated, this research may change the treatment paradigm focused on alpha-synuclein reduction for Parkinson's disease."

The study will be discussed at 5 p.m. EST, March 20 at the 2013 American Academy of Neurology (AAN) Annual Meeting in San Diego. This research is one example of the collaborative efforts between NorthShore and Mayo Clinic under the Mayo Clinic Care Network, a unique partnership that provides NorthShore patients with access to medical resources and experts from both systems working together on their behalf.

http://www.healthcanal.com/brain-ner...ause-Harm.html

The study was funded by the National Institutes of Health, Alnylam Pharmaceuticals Inc., and Medtronic Inc.

Parkinson’s Patients May Be Harmed by Novel Treatment
By Michelle Fay Cortez - Mar 21, 2013 12:01 AM ET

One of the most promising new approaches to treating Parkinson’s disease hit a snag after researchers found early evidence it may make people worse.
The experimental technique involves reducing levels of alpha-synuclein, a protein found in clumps in the brains of people with Parkinson’s that increases the risk of the disease. Research ... shows the condition progresses more rapidly in patients with naturally low levels of the protein.
Companies including Elan Corp., Alnylam Pharmaceuticals Inc. (ALNY), NeuroPhage Pharmaceuticals Inc. and Prana Biotechnology Ltd. (PBT) have early-stage efforts under way to develop drugs aimed at alpha-synuclein. The Michael J. Fox Foundation has put more than $47 million into research targeting the protein. The results suggest patients in clinical trials to lower alpha- synuclein may be at risk, said Demetrius Maraganore, a study author.
“There is a sense of urgency related to their safety,” Maraganore,...said... “If this work is reproducible and our interpretation of the findings is correct, this has immediate relevance to people with Parkinson’s.”...
Lewy Bodies
Alpha-synuclein is the main component of protein clumps, called Lewy bodies,... Researchers have been scrambling to find ways to block the alpha-synuclein protein since 1997, when scientists from the U.S. National Institutes of Health showed it caused an inherited form of the disease.
Affiris GmbH, a closely held company based in Vienna, last year began the first trial for a vaccine against alpha-synuclein in 32 patients. The vaccine, dubbed PD01A, was touted for its potential to yield the first treatment for the cause of Parkinson’s disease.
Drugmakers may want to slow their development efforts while other researchers examine and try to replicate the new findings, said Maraganore...
The study examined the progression of 1,098 patients who had their DNA sequenced at the Mayo Clinic and were contacted as many as 15 years later to determine how they were faring.
Alnylam Approach
Alnylam, based in Cambridge, Massachusetts, licensed alpha- synuclein technology from the Mayo Clinic and is developing a product that would be delivered directly into the brains of patients. Animal studies showed the approach silenced the target gene and cut protein levels 40 percent to 50 percent....
The results of the study in patients with low levels of alpha-synuclein were stunning because they were the opposite of what was expected, Maraganore said. Earlier work found people who were genetically programmed to make more of the protein had twice the risk of developing Parkinson’s disease. Once they have the disease, making less of the protein seems to speed up their demise, Maraganore said.
http://www.bloomberg.com/news/2013-0...treatment.html

Thanks for posting this....I seem to remember the same doggone thing happened in Alz. research with the protein they were targeting there....reduce that protein's plaques/tangles/whatever you want to call them....and people got worse. And fast.

I have always wondered if maybe the a-syn was formed as a protective mechanism...but never read anything to support this. Complicating things is the fact that they have found lewy bodies (the name for the clumps of a-syn, if I'm not mistaken) in people who never had symptoms of PD and they have not found them in people were diagnosed and being treated for PD.

Is the data reliable ?

If these drugs work -- Medtronic DBS is out of business.

The presence of lewy bodies in the brain upon autopsy has long been the only way to actually confirm a Parkinson's diagnosis. More recently, and supporting "Braak's staging", autopsies have shown lewy bodies more widely distributed, including in the gut.

From what I have read and been told, a-syn is a key to PD, but it is still unknown whether it's presence is protective or damaging.

Alpha Syneclein is a high priority target for PD drug development. More info on this finding in context can be found at our blog.

https://www.michaeljfox.org/foundati...e-in-parkinson

Debi