Parkinson’s breakthrough could slow disease progression
October 25, 2012
Parkinson’s, the second most common neurodegenerative disease, is caused by the death of dopamine neurons, resulting in tremors, rigidity and difficulty moving. Current treatments target the symptoms but do not slow the progression of the disease.
The compounds work by blocking calcium. The compounds target and shut a relatively rare membrane protein that allows calcium to flood into dopamine neurons.
Previously published research by D. James Surmeier, chair of physiology at Northwestern University Feinberg School of Medicine, showed that calcium entry through this protein stresses dopamine neurons, potentially leading to premature aging and death. He also identified the precise protein involved — the Cav1.3 channel.
“These are the first compounds to selectively target this channel,” Surmeier said. “By shutting down the channel, we should be able to slow the progression of the disease or significantly reduce the risk that anyone would get Parkinson’s disease if they take this drug early enough.”
“We’ve developed a molecule that could be an entirely new mechanism for arresting Parkinson’s disease, rather than just treating the symptoms,“ said Richard B. Silverman, the John Evans Professor of Chemistry at the Weinberg College of Arts and Sciences and inventor of the molecule that became the well-known drug Lyrica.
The compounds work in a similar way to the drug isradipine, for which a Phase 2 national clinical trial with Parkinson’s patients –– led by Northwestern Medicine neurologist Tanya Simuni, M.D. — was recently completed. But because isradipine interacts with other channels found in the walls of blood vessels, it can’t be used in a high enough concentration to be highly effective for Parkinson’s disease. (Simuni is the Arthur C. Nielsen Professor of Neurology at the Feinberg School and a physician at Northwestern Memorial Hospital.)
The challenge for Silverman was to design new compounds that specifically target this rare Cav1.3 channel, not those that are abundant in blood vessels. In Surmeier’s lab, the drug developed by Silverman and Soosung Kang, a postdoctoral associate in Silverman’s lab, was tested by graduate student Gary Cooper in regions of a mouse brain that contained dopamine neurons. The drug did precisely what it was designed to do, without any obvious side effects.
“The drug relieved the stress on the cells,” Surmeier said.
For the next step, the Northwestern team has to improve the pharmacology of the compounds to make them suitable for human use, test them on animals and move to a Phase 1 clinical trial.
“We have a long way to go before we are ready to give this drug, or a reasonable facsimile, to humans, but we are very encouraged,” Surmeier said.
The research was supported by the Michael J. Fox Foundation and the RJG Foundation.