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 presented at the American Academy of Neurology meeting in San Diego shows the condition progresses more rapidly in patients with naturally low levels of the protein.
Companies including Elan Corp., Alnylam Pharmaceuticals Inc., NeuroPhage Pharmaceuticals Inc. and Prana Biotechnology Ltd. 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, who is chairman of neurology at NorthShore University Health System in Evanston, Illinois, said in a telephone interview. “If this work is reproducible and our interpretation of the findings is correct, this has immediate relevance to people with Parkinson’s.”
The study released yesterday found patients with a genetic variant that led to the lowest production of alpha-synuclein were 23 percent more likely to develop dementia or need a wheelchair than those who made the most of it.
Alpha-synuclein is the main component of protein clumps, called Lewy bodies, found in everyone with Parkinson’s. 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. His brother, John Maraganore, is the chief executive officer of Alnylam, which funded the $140,000 trial with the NIH and Medtronic Inc.
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, 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.
Parkinson’s is a progressive neurological disorder that causes body tremors, the loss of muscle control and impaired movement, according to the NIH. There is no cure. A variety of medicines provide relief from symptoms for the estimated 10 million people worldwide with the disease.
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.
Like other compounds, including blood sugar, the amount needed for optimal health probably varies over time, he said. The protein may play a critical role in maintaining and repairing connections in the brain, though a surge of it coming after an injury may overwhelm the brain cells, he said.
“It’s a protein that is probably critical for healthy nerve function, so that too little or too much at different points in time can be harmful,” he said. “We may be saving a lot of patients from harm and pharmaceutical companies from wasting their money on a failed treatment strategy.”