NIH Researchers Create Comprehensive Collection of Approved Drugs to Identify New Therapies for Rare and Neglected Diseases
Posted Apr 27 2011 5:48pm
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 Healths 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 NCGCs 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
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 .