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Study identifies potential drug target
for Huntington's disease
Blocking enzyme action could protect
against energy depletion in several disorders
BOSTON - July 28, 2006 - An enzyme known to be critical for
the repair of damaged cells and the maintenance of cellular energy
may be a useful target for new strategies to treat Huntington's
disease (HD) and other disorders characterized by low cellular energy
levels. In the August issue of Chemistry & Biology, a
research team from the MassGeneral
Institute for Neurodegenerative Disease (MIND) describes their
discovery of a novel inhibitor of Poly (ADP-ribose) polymerase (PARP1)
and their findings that PARP1 inhibitors can protect HD-affected
cells from damage in laboratory assays.
"While PARP1 is essential for the repair of damaged DNA, we
also know that, if overactivated, it can cause cell death by excessive
energy depletion," says Aleksey Kazantsev, PhD, director of
the MIND High Throughput Drug Screening Laboratory, who led the
current study. "It has recently been shown that neurons from
patients with Huntington's appear to be energy-deficient, so we
hypothesized that modest stresses that would be tolerated by healthy
cells could send HD cells below a viable energy threshold and that
blocking PARP1 activation could be protective."
To test this hypothesis the MIND researchers first ran a computer
search of their small-molecule library for potential novel inhibitors
of PARP1, searching for those with structural similarities to known
inhibitors. "Safety and efficacy of human drugs depends on
many factors, so it's hard to predict which inhibitor would be most
effective against a specific disorder. The more diverse novel inhibitors
can be identified, the more chances there are of developing safe
and effective drugs," Kazantsev explains.
Two candidate molecules were identified as potential PARP1 inhibitors
based on their structure, and both of them were confirmed to inhibit
the enzyme's activity in an in vitro assay. However, when tested
using cultured human and rat cells, only one of the candidate molecules,
K245-14, successfully prevented the death of cells in which PARP1
had been overactivated.
The next assays examined whether blocking PARP1 activity with K245-14
could reduce energy depletion in cells with the HD genetic mutation.
Using cells from human HD patients and from a mouse model of the
disorder, the MIND researchers compared the reactions of HD cells
to oxidative stress caused by the application of hydrogen peroxide
with the reactions of normal cells. Although all of the cells reacted
with a loss of ATP, a key source of cellular energy, the HD cells
- which had much lower ATP levels to begin with - were much more
vulnerable to stress-induced energy loss. Inhibiting PARP1 by means
of K245-14 reduced ATP loss in all tested cells and significantly
protected against both energy loss and cell death in the HD cells.
"While we were pleased to observe these predicted protective
effects in our experiments, validation of PARP1 as a useful HD drug
target will require the testing of inhibitors in animal trials,"
Kazantsev explains. "The process of identifying the best candidates
for trials will be very complex, since any drug treating a central
nervous system disorder needs to penetrate the blood-brain barrier.
We will be working with our collaborators at the Scripps Research
Institute - world leaders in computational chemistry - to conduct
a more comprehensive virtual screen and select additional promising
candidates for drug development.
"Inhibition of PARP1 activity is thought to be potentially
beneficial for treatment of cancer, neurodegenerative conditions
such as Parkinson's disease, and over twenty other human disorders,"
he adds. "We envision broad therapeutic applications for small
molecule inhibitors of PARP1." Kazantsev is an assistant professor
of Neurology at Harvard Medical School.
The first author of the Chemistry & Biology report is
Stephen Altmann of MIND. Additional co-authors are Michele Maxwell,
PhD, Francine Norflus, PhD, Jonathan Fox, PhD, Steven Hersch, MD,
PhD, and Anne Young, MD, PhD, of MIND and the MGH Department of
Neurology; Elisa Fossale and Marcy MacDonald, PhD, of the MGH Center
for Human Genetic Research; and Andrey Muryshev, PhD, and Ruben
Abagyan, PhD, Scripps Research Institute, La Jolla, California.
The study was supported by the National Institutes of Health and
the Huntington's Disease Society of America.
Massachusetts General Hospital, established in 1811, is the original
and largest teaching hospital of Harvard Medical School. The MGH
conducts the largest hospital-based research program in the United
States, with an annual research budget of nearly $500 million and
major research centers in AIDS, cardiovascular research, cancer,
computational and integrative biology, cutaneous biology, human
genetics, medical imaging, neurodegenerative disorders, regenerative
medicine, transplantation biology and photomedicine. MGH and Brigham
and Women's Hospital are founding members of Partners HealthCare
HealthCare System, a Boston-based integrated health care delivery
system.
Media Contact: Sue
McGreevey, MGH Public Affairs
Physician Referral Service: 1-800-388-4644
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