NORTHWESTERN (US) — A new family of compounds slows the progression of Parkinson’s disease by slamming the door on calcium.
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 new compounds target and shut a relatively rare membrane protein that allows the destructive calcium to flood into dopamine neurons. Previously published research showed that calcium entry through this protein stresses dopamine neurons, potentially leading to premature aging and death. The earlier research identified the precise protein involved—the Cav1.3 channel.
“These are the first compounds to selectively target this channel,” says D. James Surmeier, chair of physiology at Northwestern University Feinberg School of Medicine. “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,” adds co-author Richard B.Silverman, professor of chemistry.
As reported in the October 23 Nature Communications, 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—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.
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. He and colleagues first used high-throughput screening to test 60,000 existing compounds, but none did the trick.
“We didn’t want to give up,” Silverman says. He then tested some compounds he had developed in his lab for other neurodegenerative diseases. After Silverman identified one that had promise, Soosung Kang, a postdoctoral associate in Silverman’s lab, spent nine months refining the molecules until they were effective at shutting only the Cav1.3 channel.
In Surmeier’s lab, the drug developed by Silverman and Kang 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 says.
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, Surmeier says.
“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.”
The research was supported by the Michael J. Fox Foundation and the RJG Foundation.
Source: Northwestern University