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Parkinson's Gene Therapy Wires New Brain Circuits

HealthDay News
by By Amy Norton
HealthDay Reporter
Updated: Nov 28th 2018

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WEDNESDAY, Nov. 28, 2018 (HealthDay News) -- An experimental gene therapy for Parkinson's disease seems to work by rewiring key areas of the brain, a new study finds.

The researchers focused on 15 Parkinson's patients who, in an earlier trial, had received so-called GAD gene therapy. GAD is an enzyme that spurs the production of a brain chemical involved in movement control.

In the previous trial, patients had shown improvements in their movement problems after receiving infusions of the GAD gene into the brain.

What hadn't been clear was precisely why, said researcher Dr. David Eidelberg, who directs the Center for Neurosciences at the Feinstein Institute for Medical Research, in Manhasset, N.Y.

So for the new study, Eidelberg's team examined specialized brain scans from 15 of the trial patients. The investigators found an unexpected answer: The gene therapy did not change the abnormal brain circuitry that marks Parkinson's disease.

Instead, it essentially rewired a small area of the brain, to partially compensate for the faulty circuitry.

"It created its own set of circuits," Eidelberg explained. "The disease circuitry continues -- so this is not a cure."

Still, he said, the gene therapy seems to spur new brain connections that can benefit people with Parkinson's.

The study findings were published online Nov. 28 in Science Translational Medicine.

Parkinson's disease affects nearly 1 million people in the United States alone, according to the Parkinson's Foundation.

The root cause is unclear, but as the disease progresses, the brain loses cells that produce dopamine -- a chemical that regulates movement. As a result, people suffer symptoms like tremors, stiff limbs, and balance and coordination problems that gradually worsen over time.

There are treatments to lessen those symptoms, including medications that boost dopamine levels or mimic the actions of dopamine. Another option for some patients is deep brain stimulation (DBS), where electrodes are implanted in a specific brain area to deliver continuous electrical pulses. It's thought to help by suppressing abnormal electrical activity.

GAD gene therapy is done by inserting the gene into an inactivated cold virus. That viral "vector" is infused into a specific brain area called the subthalamic nucleus -- which is one of the brain regions targeted in DBS treatment.

Originally, Eidelberg added, researchers thought the gene therapy would work in a "DBS-like" way.

But based on the new findings, that's not the case.

Dr. Michael Okun is medical director of the Parkinson's Foundation. He called the study "fascinating."

"It showed that GAD gene therapy, unlike subthalamic nucleus DBS, did not change the expected Parkinson's disease brain network," Okun said. "Instead, it co-opted adjacent non-motor pathways."

Why does that matter? One reason, according to Okun, is that it offers an "important lesson" for the gene therapy field going forward.

Researchers cannot make assumptions about a therapy's "mechanism of action," he said, based on the brain area it targets.

Eidelberg made another point: In future studies, researchers could use brain imaging to be sure that patients' symptom improvements are due to a true effect of the gene therapy -- rather than a "placebo effect."

In the original trial, which involved a few dozen Parkinson's patients, some were randomly assigned to receive GAD gene infusions. The rest underwent a "sham" procedure for comparison.

Over six months, both groups showed improvements in movement symptoms like stiffness and tremor. But the gene therapy group saw greater gains.

"It wasn't a slam dunk," Eidelberg stressed. "But they were doing better. And that persisted to the one-year mark."

With any such therapy, there is a theoretical concern that the infused gene will have unintended effects.

"What we've seen is that this gene stays put," Eidelberg said. "It doesn't percolate all over the brain."

In the original trial, there were no red flags, according to the researchers. The most common side effects were temporary headaches and nausea.

Various research teams are looking at different approaches to gene therapy for Parkinson's. The hope, Eidelberg said, is to develop additional options that work for at least some patients -- possibly freeing them from taking daily medications.

At this point, he noted, there is "a lot of interest" in doing a larger, later-stage trial of the GAD therapy. But none has begun yet.

The current study was funded by Neurologix Inc., the company that developed the gene therapy.

More information

The Parkinson's Foundation has more on Parkinson's treatment.