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Geoff Spencer, NHGRI
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NIH researchers create comprehensive collection of approved drugs to identify new therapies for rare and neglected diseases
Researchers have begun screening the first definitive collection of thousands of approved drugs for clinical use against rare and neglected diseases. They are hunting for additional uses of the drugs hoping to find off-label therapies, for some of the 6,000 rare diseases that afflict 25 million Americans. The effort is coordinated by the National Institutes of Health’s Chemical Genomics Center (NCGC).
"This is a critical step to explore the full potential of these drugs for new applications," said NIH Director Francis S. Collins, M.D., Ph.D. "The hope is that this process may identify some potential new treatments for rare and neglected diseases."
The researchers assembled the collection of approved drugs for screening based on information from the NCGC Pharmaceutical Collection browser at http://tripod.nih.gov/npc. This publicly available, Web-based application described in a paper appearing in the April 27 issue of Science Translational Medicine, provides complete information on the nearly 27,000 active pharmaceutical ingredients including 2,750 small molecule drugs that have been approved by regulatory agencies from the United States, Canada, Europe and Japan, as well as all compounds that have been registered for human clinical trials.
“In order to launch a systematic repurposing effort using NCGC’s drug screening technologies, we needed access to a comprehensive collection of clinically approved drugs,” said Christopher P. Austin, M.D., director of NCGC, which is currently administered by the National Human Genome Research Institute (NHGRI). “Our team took on the monumental task of assembling this collection, making it publicly available and creating a world class resource.”
The NCGC Pharmaceutical Collection (NPC) browser provides users with the ability to explore drugs by name, chemical structure, approval status and indication. Groups interested in developing their own screening collections can leverage the supplier and catalog information provided in the browser. The browser, which is an ongoing effort, also includes entries on investigational drugs. The ultimate goal is to collect all of the more than 7,500 compounds that have been tested in man and which present potential jump-start development of treatments for rare and neglected diseases.
The current focus is on collaborating with disease foundations, industry, and academic investigators with disease-relevant assays to screen against the approved drug collection acquired by NCGC. Any new therapeutic use of an approved drug would require additional studies including clinical trials in that disease, approved by the U.S. Food and Drug Administration. Given the cost and limited quantities of the drugs in the collection, each partnership to screen the NPC will be evaluated based on the quality of each disease-related assay and its scientific merit.
Creating a new drug is expensive. Recouping the investment can be difficult for rare diseases, due to the small number of patients with the disease or, in the case of tropical neglected diseases, the limited ability of patients to pay for treatments. Today, therapies are available for less than 300 rare diseases.
Drugs that receive regulatory approval have been demonstrated to be reasonably safe and effective in the treatment of a specific disease or condition. When such drugs are used in large populations, new benefits or adverse effects can be discovered. Subsequently, the use of approved drugs can be expanded beyond what a drug was originally approved for to treat other health conditions.
Thalidomide is an example of repurposing a drug with serious adverse effects in one condition to treat another disease, according to the authors. In the 1950s, it was used as a sedative and as a treatment for morning sickness during pregnancy. It was later withdrawn because it was found to cause severe birth defects. Thalidomide was then repurposed for use against leprosy, an infectious disease causing skin lesions and multiple myeloma, a cancer of plasma cells, which are a type of white blood cell present in bone marrow.
Based on the drug's new application, the U.S. Food and Drug Administration approved thalidomide for the treatment of leprosy in 1998 and for multiple myeloma patients in 2006.
More recently, a team of NHGRI researchers used a similar approach, examining patient blood samples to see what gene and protein networks were active in a syndrome called periodic childhood fever associated with aphthous stomatitis, pharyngitis and cervical adenitis — or PFAPA. PFAPA causes monthly flare-ups of fever, accompanied by sore throat, swollen glands and mouth lesions.
The researchers detected overactive genes in the patient's immune response, including interleukin-1, a molecule that is important in triggering fever and inflammation. From these data, the researchers hypothesized that anakinra, a drug that prevents interleukin-1 from binding to its receptor, could be therapeutic. They injected anakinra into five children on the second day of their PFAPA fevers and all showed a reduction in fever and inflammatory symptoms within hours.
Another approach that does not require a complete knowledge of a disease or drug mechanism uses high-throughput drug screening technologies that screen drugs for biological activity in cell-based models of disease. Drugs that record an activity are known as hits and can be further studied for their therapeutic potential by researchers in animal models of the disease and eventually in human clinical trials.
NCGC already has screened the approved drug collection against more than 200 cell-based models of disease. In every screen, NCGC characterizes the pharmacology of each compound over a wide range of concentrations using its signature quantitative high-throughput screening approach. All of the data from NCGC screens will be published and made publicly available.
In addition to repurposing drugs, the NCGC plans to screen the collection as part of the Tox21 initiative to better predict and model adverse effects associated with approved drugs. Drug toxicity is one of the primary reasons that approved drugs are removed from the marketplace and the ability to predict toxicity would dramatically improve the efficiency of drug development.
The National Human Genome Research Institute is one of the 27 institutes and centers at the NIH, an agency of the Department of Health and Human Services. The NHGRI Division of Intramural Research develops and implements technology to understand, diagnose and treat genomic and genetic diseases. Additional information about NHGRI can be found at its website, www.genome.gov.
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 www.nih.gov.
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NIH researchers create comprehensive collection of approved drugs to identify new therapies for rare and neglected diseases, April 27, 2011 News Release - National Institutes of Health (NIH)
NIH researchers identify cause and new treatment for common recurrent fever in children
Therapy for periodic fever syndrome targets the body's immune response
Bethesda, Md., Fri., April 8, 2011 — A preliminary study conducted by a team at the National Institutes of Health has identified a promising new treatment in children for the most common pediatric fever disease in children. The syndrome is called periodic fever associated with aphthous stomatitis, pharyngitis and cervical adenitis — or PFAPA — and is characterized by monthly flare-ups of fever, accompanied by sore throat, swollen glands and mouth lesions.
The proposed treatment, which will be validated in a larger study before it is recommended in treating PFAPA syndrome, wards off an inappropriate immune system attack without increasing the frequency of flare-ups, a problem caused by the current standard treatment with corticosteroids. The team of researchers from the National Human Genome Research Institute (NHGRI) and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) reported their findings in the April 8, 2011, early online edition of the Proceedings of the National Academy of Sciences.
"Until now, the basis of PFAPA has been a mystery," said senior author and NHGRI Scientific Director Daniel Kastner, M.D., Ph.D. "Advances in genomic analysis have allowed us to define a major role for the innate immune system, the body's first line of defense against infection. Targeting a specific product of white blood cells at the first sign of fever appears to abort the attacks."
Children with PFAPA syndrome experience attacks of fever, each lasting three to six days, usually three to eight weeks apart. Their predictability is so regular that parents have been known to make pediatric appointments a week ahead of when they expect their child to experience a PFAPA episode. Affected children experience their first attack before the age of 5, with fever episodes usually abating in adolescence or young adulthood. The only remedy for PFAPA, besides corticosteroids, is removal of an affected child's tonsils, which has a good rate of success in eliminating PFAPA syndrome, but is an invasive alternative.
The new experimental treatment resulted from the researchers using a systems biology approach, which entailed gene and protein expression and cell biology analysis in carefully selected patient and healthy control subjects, to determine the underlying disturbance of the immune system. They analyzed patient blood samples to detect which gene and protein networks are involved in the cell signaling and metabolic pathways activated in the disease.
The research group studied 21 patients with PFAPA syndrome along with an equal number of healthy children and 12 children with a distinctly different set of hereditary fever syndromes. They analyzed gene expression during episodes of fever and intervening periods when the children were well. The analysis revealed gene expression profiles that uniquely identified PFAPA immune response.
"Gene profiles during PFAPA flares are remarkably distinct from when children are asymptomatic," said Dr. Kastner, noting that the analysis also distinguished PFAPA syndrome from other periodic fevers. But when PFAPA patients are asymptomatic, their gene expression is similar to healthy children.
During PFAPA flare ups, the researchers detected activation of both forms of immune response — the innate, first-line-of-defense immunity, and adaptive immunity, which is the body's ability to detect and remember an infection in order to fight it later. This dual response supports the idea that the fevers of PFAPA are an immunologic response to some external stimulus, possibly related to microbial infection.
The researchers looked for biological markers that would indicate the onset of a flare-up of fever in children with PFAPA. During PFAPA flare-ups, the researchers detected decreased numbers of activated T cells, white blood cells that play a role in the cell's innate immune response. They suspect that these activated T cells migrated to the lymph nodes in the neck, where they accumulate. They also detected over-expression of genes activated in innate immune responses, including interleukin-1, a molecule that is important in triggering fever and inflammation.
From these data, the researchers hypothesized that anakinra, a drug that prevents interleukin-1 from binding to its receptor, could be therapeutic. They administered anakinra by injection to five children on the second day of their PFAPA fevers and all showed a reduction in fever and inflammatory symptoms within hours.
"The anakinra treatment has the potential to restore these children to a mostly symptom-free childhood," said Dr. Kastner. "The comprehensive analysis of gene expression during PFAPA attacks would not have been possible without the tools created by the Human Genome Project, and the possibility of an effective treatment is yet another of the genome project's many dividends."
A larger clinical trial for the use of anakinra in treating this periodic fever syndrome is planned, Dr. Kastner said.
NHGRI is one of the 27 institutes and centers at the NIH, an agency of the Department of Health and Human Services. The NHGRI Division of Intramural Research develops and implements technology to understand, diagnose and treat genomic and genetic diseases. Additional information about NHGRI can be found at its website, www.genome.gov.
The mission of the NIAMS, a part of the U.S. Department of Health and Human Services' National Institutes of Health (NIH), is to support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. For more information about the NIAMS, call the information clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS website at www.niams.nih.gov.
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 www.nih.gov.
Contact
Raymond MacDougall, NHGRI
301-402-0911
macdougallr@mail.nih.gov
Genome.gov | 2011 News Release; NIH researchers identify cause and new treatment for the most common periodic fever disease in children
Genome.gov | 2011 News Release; NIH researchers identify cause and new treatment for the most common periodic fever disease in children
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