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Wednesday, July 25, 2018

Drugs aimed at a sliver of Parkinson’s patients may benefit many more than thought — and boost a biotech

By SHARON BEGLEY      JULY 25, 2018

Healthy brains (top) have low levels of a damaging enzyme, shown in glowing red and gray in the center and right panels, while Parkinson's brains (bottom) have high levels. The far left panels show dopamine neurons.GREENAMYRE LAB


It’s Christmas in July for at least one small biotech and, possibly, some major pharmaceutical companies. They had assumed a class of drugs they’re developing might work in a rare, genetic form of Parkinson’s disease that accounts for 3 or 4 percent of cases. But, according to surprising research published on Wednesday, the molecule that the drugs target might also be involved in the more common, non-inherited form of Parkinson’s.

“Their potential market just increased 30-fold,” said Dr. J. Timothy Greenamyre, a neurologist and Parkinson’s expert at the University of Pittsburgh and senior author of the new study. “[The experimental therapies] may benefit everybody with this disease.”

His results, reported in Science Translational Medicine, are preliminary, the Parkinson’s drugs in development are no further along than early clinical trials, and some studies raise doubts that they’ll be safe and effective. But the idea that a gene called LRRK2 (pronounced “lark 2”) that can cause Parkinson’s when it is mutated can also do so in its normal form offers hope that treatments targeting inherited Parkinson’s might be effective across the board.

“This is a striking finding that shows how normal LRRK2 may contribute to the development of Parkinson’s disease,” said Beth-Anne Sieber of the National Institute of Neurological Disorders and Stroke, part of the National Institutes of Health, which partly funded the research.

In 2004 scientists in Germany and Spain discovered that when LRRK2 has any of several mutations it can cause an inherited form of the devastating brain disorder, whose causes are otherwise largely unknown. Located on chromosome 12, the gene codes for the production of a kind of enzyme called a kinase, also named LRRK2.

The mutations make the kinase abnormally active. Since the kinase has more responsibilities than Jared Kushner (it moves molecules across cell membranes, keeps mitochondria functioning, and helps the cell’s garbage disposal, among other jobs) a hyper-activated version spells trouble.

Using a molecular tag that glows fluorescent red if an enzyme is active, the Pittsburgh scientists found that the brains of seven people who had died of Parkinson’s were awash in hyper-activated LRRK2. Their dopamine neurons (which die off in Parkinson’s, causing movement and cognitive abnormalities) had enzyme levels six times that in the eight healthy brains serving as controls, especially in the substantia nigra, the brain region most damaged in Parkinson’s. Yet the Parkinson’s patients did not have LRRK2 mutations. Something else apparently goosed their LRRK2.

The scientists also searched for hyper-activated LRRK2 in the neurons of lab rats that developed Parkinson’s after being exposed to the pesticide rotenone, a suspected cause of the disease. There, they also found “a dramatic increase,” Greenamyre said. Together, the human and rat findings “surprised and intrigued us.”
Although only mutated LRRK2 genes had previously been linked to Parkinson’s, the human and rat results suggest that even non-mutated LRRK2 can become abnormally activated (possibly by exposure to pesticides or other toxic hits) and cause the disease. That means lowering LRRK2 activity could treat more than just the inherited form of Parkinson’s.

One effect of hyper-activated LRRK2 is to cripple other vital molecules, including those that recycle the components of dead cells into new cells. “All of these molecules become inactivated by LRRK2,” preventing them from doing their jobs and perhaps contributing to Parkinson’s disease, Greenamyre said. In addition, hyper-activated LRRK2 seems to play a role in letting a Parkinson’s-related protein called alpha-synuclein form neuron-killing clumps known as Lewy bodies, a hallmark of the disease and a cause of the severe cognitive impairments it brings.

At least a dozen compounds that inhibit LRRK2 activation have been developed, with the idea that they might be effective in the inherited cases of Parkinson’s, where mutations cause that hyper-activation. If such activation also occurs in non-inherited Parkinson’s, the compounds might work there, too.

Andrew West of the University of Alabama, Birmingham, called LRRK2 one of “the most exciting druggable targets to slow and stop [Parkinson’s] disease.” But some patients will benefit more than others from LRRK2-targeting drugs, he predicted: In his Parkinson’s clinic, only about 20 percent of patients with the non-inherited form “appear to have over-active or over-expressed LRRK2.”

And finding such drugs will not be easy. The Pittsburgh scientists tested an LRRK2 inhibitor from Pfizer: Called PF-360, it stopped LRRK2 from being activated by the pesticide rotenone in rats’ dopamine neurons and thereby blocked its neurotoxic effects. At UAB, West and his colleagues have also found that inhibiting mutant LRRK2 with one of the Pfizer compounds reduced alpha-synuclein in mice. But other studies in lab animals have found no such benefit from LRRK2 inhibitors, and some of the drugs seem to alter lung and kidney cells.

GlaxoSmithKline continues to develop a LRRK2 inhibitor for Parkinson’s, said spokeswoman Mary Anne Rhyne. But it is in very early (nonhuman) studies and, with Pfizer eliminating its Parkinson’s R&D this year, biotech start-up Denali Therapeutics has scooted ahead.

Last December Denali announced some success in its phase 1 trial of a LRRK2 inhibitor, called DNL-201. In healthy volunteers, the drug inhibited some 90 percent of LRRK2’s activity at the highest dose levels; the company expects to announce final safety data in a few weeks, said Dr. Carole Ho, Denali’s chief medical officer. In March, the company dosed its first patient in a clinical trial of a second LRRK2 inhibitor, DNL-151, in the Netherlands.

After it has safety data on both, the South San Francisco, Calif., company will decide which drug to start testing in Parkinson’s patients, Ho said, adding that the market could well be greater than expected. “We believe that inhibition of LRRK2 kinase may have therapeutic potential” in the common form of Parkinson’s, she said, and not only that caused by LRRK2 mutations.

Sharon Begley

Senior Writer, Science and Discovery
Sharon covers science and discovery.

https://www.statnews.com/2018/07/25/parkinsons-disease-drugs-may-benefit-more-patients/

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