August 22, 2016

Gene Therapy produces Dopamine in the Brain as path to Parkinsons treatment

Parkinson’s patients who take the drug levodopa, or L-Dopa, are inevitably disappointed. At first, during a “honeymoon” period, their symptoms (which include tremors and balance problems) are brought under control. But over time the drug becomes less effective. They may also need ultrahigh doses, and some start spending hours a day in a state of near-frozen paralysis.

A biotech company called Voyager Therapeutics now thinks it can extend the effects of L-Dopa by using a surprising approach: gene therapy. The company, based in Cambridge, Massachusetts, is testing the idea in Parkinson’s patients who’ve agreed to undergo brain surgery and an injection of new DNA.

Parkinson’s occurs when dopamine-making neurons in the brain start dying, causing movement symptoms that afflicted boxing champ Muhammad Ali and actor Michael J. Fox, whose charitable foundation has helped pay for the development of Voyager’s experimental treatment.

The cause of Parkinson’s isn’t well understood, but the reason the drug wears off is. It’s because the brain also starts losing an enzyme known as aromatic L-amino acid decarboxylase, or AADC, that is needed to convert L-Dopa into dopamine.

Voyager’s strategy, which it has begun trying on patients in a small study, is to inject viruses carrying the gene for AADC into the brain, an approach it thinks can “turn back the clock” so that L-Dopa starts working again in advanced Parkinson’s patients as it did in their honeymoon periods.

Videos of patients before and after taking L-Dopa make it obvious why they’d want the drug to work at a lower dose. In the ‘off’ state, people move in slow motion. Touching one’s nose takes an effort. In an ‘on’ state, when the drug is working, they’re shaky, but not nearly so severely disabled.

“They do well at first but then respond very erratically to L-Dopa,” says Krystof Bankiewicz, the University of California scientist who came up with the gene-therapy plan and is a cofounder of Voyager. “This trial is to restore the enzyme and allow them to be awakened, or ‘on,’ for a longer period of time.”

A new trial under way, this one being carried out by Voyager, is designed to get much higher levels of DNA into patients’ brains in hopes of achieving better results. To do that, Bankiewicz developed a system to inject the gene-laden viral particles through pressurized tubes while a patient lies inside an MRI scanner. That way, the surgeon can see the putamen, the brain region where the DNA is meant to end up, and make sure it’s covered by the treatment.

There are other gene therapies for Parkinson’s disease planned or in testing. A trial developed at the National Institutes of Health seeks to add a growth factor and regenerate cells. A European company, Oxford BioMedica, is trying to replace dopamine.

Altogether, as of this year, there were 48 clinical trials under way of gene or cell replacement in the brain and nervous system, according to the Alliance for Regenerative Medicine, a trade group. The nervous system is the fourth most common target for this style of experimental treatment, after cancer, heart disease, and infections.

SOURCES- Technology Review

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