JULY 25, 2018
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.
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