Can An Experimental Drug Rewire the Brain to Treat Parkinson’s?

About a decade ago, a young biomedical researcher at Columbia University Vagelos College of Physicians and Surgeons came up with a novel idea for treating Parkinson’s disease.

The proposed treatment—an amino acid that occurs naturally in the body—had almost everything working in its favor: it not just slowed but reversed the course of the disease in mice; it showed promise in a small clinical trial; it appears safe for human use; it could be taken orally; and it was cheap to manufacture.

But the potential remedy had a fateful flaw: as a naturally occurring substance, it couldn’t be patented. With little profit to be made, no pharmaceutical or biotech company would invest the millions needed to support a clinical trial. And so the potential treatment languished on a laboratory shelf.

“It was frustrating,” says David Sulzer, professor of neurobiology (in the departments of psychiatry, neurology, and pharmacology), who supervised and collaborated with the postdoc behind the therapy. “We could have started testing it 10 years ago.”

Despite setbacks, Sulzer never stopped advocating for the therapy, just recently attracting support from SPARK NS, an independent nonprofit organization dedicated to efficiently advancing promising academic discoveries in neuroscience from the lab to the clinic. With funding and other support including education, mentorship from industry expert advisors, and networking opportunities as part of a two-year translational research program from SPARK NS, Sulzer hopes to launch at least a modest clinical trial of the amino acid—D-serine—and give this potential Parkinson’s therapy a second chance.

D-serine may rewire the brain

The story of D-serine begins in 2013, when Sulzer’s postdoc, Yvonne Schmitz, realized that it might be possible to rewire the brain to correct abnormalities in Parkinson’s.

In the healthy brain, movement is partly controlled by neurons that stretch from the base of the brain into the brain’s central movement center. In this center, the neurons release dopamine, which initiates physical movements and controls their timing. In Parkinson's, these neurons gradually wither and die, starving the brain’s movement center of dopamine, leading to tremors, stiffness, and slowed movements.

The standard therapy for Parkinson’s—L-DOPA—replenishes the dopamine supply, reducing the disease’s symptoms. But L-DOPA’s effectiveness wanes after a few years. Another therapy, deep-brain stimulation, in which electrodes are implanted in the brain to deliver electronic pulses to the brain’s movement center, can work well, but it’s costly, extremely invasive, and not suited for every patient.

Schmitz may have come up with an alternative. In short, she learned that a different set of dopamine-producing neurons—called VTA neurons—can be rerouted to stimulate the brain’s movement center. Normally, VTA neurons (which aren’t affected by Parkinson’s) reach into a different, nearby part of the brain.

But as Schmitz demonstrated in a mouse model of Parkinson’s, the addition of D-serine stimulates some VTA neurons into growing branches that extend into the brain’s movement center and deliver enough dopamine to restore the lost neuromuscular functions. In the mice, this process was impressively rapid, requiring less than a month of treatment.

Hints of success from psychiatry

Sulzer and Schmitz never had the opportunity to test D-serine in patients, but their colleagues in Columbia’s psychiatry department did. With no knowledge of Sulzer and Schmitz’s work, Daniel Javitt collaborated on a small trial of D-serine as a treatment for apathy and depression in 10 patients with Parkinson’s. Their psychiatric symptoms improved, but surprisingly, so did their motor symptoms. “Our colleagues didn’t know why. They didn’t have a mechanism,” says Sulzer. “But we do.”

The details of Sulzer’s D-serine trial have yet to be determined. “We think it has a lot of potential and we’re excited to be doing a trial of any kind, even a small one,” he says.

D-serine is unlike anything that’s been tried in Parkinson’s, Sulzer adds. “D-serine is what we’ve termed ‘neurorestorative’: it changes brain circuitry to restore lost function,” he explains. “Other treatments in development for Parkinson’s aim to protect neurons from dying, which means they must be given early in the course of the disease, before the neurons are damaged.”

That’s a major drawback, since physicians don’t have a way to diagnose Parkinson's before symptoms appear. By the time patients are diagnosed, they’ve lost 80% of their dopamine neurons, and neuroprotective treatments wouldn’t have much to protect. “I think eventually we’ll have a way to detect Parkinson’s early and we’ll have effective neuroprotective treatments,” Sulzer says, “but until then we need something else.”

Sulzer’s lab is also looking for other ways—including electroconvulsive therapy (ECT)—to build new movement circuits in the brain. During her neurology residency in Germany, Anika Frank, learned that movement symptoms improved in some Parkinson’s patients treated with ECT for their depression. After learning about Sulzer’s work in this area, she applied to be a postdoc in his lab to investigate how ECT improves movement so it can be optimized for Parkinson’s patients. Her studies with Parkinson’s mice are showing that ECT appears to trigger the release of growth factors in the brain. “Mice treated with ECT become more active, and when we look in their brains, we also see the sprouting of dopamine neurons,” she says.