News Release

Monday, July 23, 2007

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

About the National Institutes of Health (NIH): 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. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit

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