Novel Approach Targets an Inherited Disorder
NIH Chemical Genomics Center Jumpstarts Drug
Development in Public Sector
Using a quantitative high-throughput screening strategy, researchers
at the National Institutes of Health (NIH) have identified three
new classes of small molecules that may prove useful for treating
Gaucher disease, an inherited disorder that disrupts a cell’s ability
to break down and dispose of certain cellular waste products. The
findings, reported in the online edition of the Proceedings
of the National Academy of Sciences during the week of July
23-27, could lead to a new therapeutic approach in which a defective
enzyme is corrected by an easy-to-take oral medication. Current
treatment for Gaucher disease requires expensive and inconvenient
intravenous enzyme infusions that control many, but not all, of
the symptoms.
“This discovery is exactly the kind of advance that I envisioned
when we launched the NIH Roadmap for Medical Research,” said Elias
A. Zerhouni, M.D., director of the National Institutes of Health. “Until
the NIH Chemical Genomics Center (NCGC) was created as part of
the Molecular Libraries Screening Center Network, researchers in
the public and academic sector lacked the tools commonly used by
the pharmaceutical industry to find leads for possible new treatments
such as these. The discovery of three new classes of compounds
to potentially reverse Gaucher disease is a proof of principle.”
Gaucher disease occurs when an individual inherits two defective
copies of the gene that carries the code for an enzyme called glucocerebrosidase.
The enzyme functions in a part of the cell known as the lysosome,
where cellular components are broken down, or metabolized, for
recycling. This particular enzyme normally metabolizes glucocerebroside,
a glycolipid (which comprises both a fatty acid and a sugar). When
the enzyme is deficient or defective, the glycolipid accumulates
in certain cells of the body; in the spleen and liver, causing
painful and disruptive swelling, and in the bone marrow, resulting
in low blood counts and bone fragility and pain. Some forms of
the disease also affect the brain and can cause neurological problems.
“Gaucher disease is one of many genetic disorders that would benefit
from an affordable life-long therapy that is easy to administer,” said
Francis S. Collins, M.D., Ph.D., director of the National Human
Genome Research Institute (NHGRI), which operates the NCGC for
NIH. “The screening strategy offers a faster and less expensive
way to develop promising leads for chemicals that may be developed
into safe and effective medicines for controlling this illness.
Moreover, the mechanism by which these newly identified compounds
reverse Gaucher may provide a new therapeutic strategy that could
be widely used for many types of diseases.”
In the study, researchers screened 60,000 individual compounds
at numerous concentrations to determine each molecule’s effect
on the ability of normal glucocerebrosidase to break down a fluorescent
version of its lipid target. To test so many compounds at once,
the NCGC used its quantitative high-throughput screening process
that uses robots to mix, monitor and display the results of each
reaction. The process not only identified which compounds had the
best activity and their optimal concentrations, but enabled the
researchers to identify groups of similar compounds that could
be modified further to optimize the effect of potential drug therapy
candidates.
“Because the NCGC robotics system allows us to screen such large
numbers of compounds at up to 15 concentrations at a time, we produced
far fewer false negatives and false positives than previous strategies,” said
Christopher P. Austin, M.D., director of the screening center and
Senior Advisor for Translational Research to the NHGRI Director. “This
is the first of what we expect to be many study results that begin
to translate basic research findings from genomics into treatments
for a wide range of important illnesses.”
The screening procedure identified three classes of compounds
that previously have not been considered as therapeutics for Gaucher
disease, including sulfonamides, which have been used as antibiotics,
aminoquinolines and triazines. In each class, there are numerous
chemically similar molecules; the challenge is to find the best
one for the treatment of individuals with Gaucher disease. To test
whether these different compounds could correct the defective enzyme,
skin cell cultures from people with Gaucher disease were treated
with the best candidates. Cells from several patients with Gaucher
disease had better enzyme activity when treated with the best compounds
from each group, and microscope studies showed that more of the
enzyme appeared to reach the lysosomes.
“These classes of molecules may actually salvage the patients’ own
defective enzyme,” said Ellen Sidransky, M.D., senior investigator
in NHGRI’s Medical Genetics Branch. “In Gaucher disease, most of
the mutations that cause the disease change a single amino acid
in the enzyme. This results in a misfolded protein, which either
doesn’t work right or is discarded before it reaches the lysosome.
The newly identified molecules, called chemical chaperones, bind
to the enzyme and stabilize its shape, enabling it to get to the
lysosome where it can then act to break down the storage products.
The screening process showed which shape-changing molecules best
restored the enzyme’s normal function.”
The next phase of the research will be to chemically modify individual
molecules within each class to optimize their activity and to reduce
potential toxicity. Although it will still be some time before
any resulting treatment is ready for the clinic, the quantitative
high-throughput screening process has greatly increased the speed
of identifying good candidates for drug development.
One complexity of treating Gaucher disease is that it is caused
by any of over 200 different alterations in the gene that makes
glucocerebrosidase. A class of medicines that works for one disease-causing
mutation may not be very effective for another. By identifying
and optimizing several classes of compounds, researchers can develop
therapies for people with different forms of the disease. This
rare disease may become one of the leading examples of how determining
a patient’s genotype — the specific mutations that cause
the disease in that person — can result in customized treatment
with just the right drug; a proof of concept for personalized medicine.
“Research into this rare disease may also lead to new treatments
for other, more common disorders, including Parkinson's disease
and a related form of dementia,” Sidransky said. Recent studies
in her laboratory have suggested a link between Parkinson's disease
and the presence of a mutation in the gene for glucocerebrosidase.
Having even one abnormal copy of the gene can lead to an increased
risk for these brain disorders. Developing a safe medicine that
reshapes the defective enzyme may also prove helpful in preventing
these other diseases in people that carry a glucocerebrosidase
mutation.
The National Human Genome Research Institute is part of the National
Institutes of Health. For more about NHGRI, visit www.genome.gov.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.
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