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Spotlight on Research 2008
January 2008 (historical)
Researchers Develop Sustained-Release Drug Carrier for Treatment of Osteoarthritis
Researchers have developed a method of modifying injectable arthritis drugs that should provide for sustained presence of the medication in the joint space. Lori A. Setton, Ph.D., and her colleagues at Duke University designed a protein fragment that aggregates, remains at the site of the injection, and forms a "drug depot." When evaluated in a rat knee joint model, the delivered protein remained in the joint over 25 times longer than a comparable soluble molecule. Dr. Setton next coupled the protein fragment with a drug in clinical development for the treatment of osteoarthritis (OA), interleukin-1 receptor antagonist (IL1-Ra). The studies were funded in part by a grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the Department of Health and Human Services' National Institutes of Health (NIH).
Recent studies have indicated that OA is caused by more than wear and tear on the joint; inflammation is caused by interleukin-1, an immune system molecule that can worsen the condition. Researchers believe that IL1-Ra, which has been used to treat autoimmune diseases, might block this immune-related inflammatory response in OA. Trials of this drug have had limited success in OA, however, because of its short half-life in the joint space.
The researchers focused on developing the appropriate form for a specific protein that will clump together at body temperatures. When combined with the target drug IL1-Ra, the molecules form drug deposits without losing the biological activity of unmodified IL1-Ra. Not only is this form expected to increase the duration of drug presence in the joint space, it might also reduce negative side effects, since the drug remains at the injection site, instead of accumulating in the bloodstream. IL1-Ra can, for example, suppress the immune system when it is distributed throughout the body; keeping it at the injection site in the joint might prevent this effect.
The study was not designed to test the effectiveness of IL1-Ra for OA, but rather to test the delivery system for protein-based drugs like IL1-Ra. Testing the effectiveness of the drug in human subjects with OA will require further investigation.
An estimated 12.1 percent of the U.S. population (nearly 21 million Americans) age 25 and older have osteoarthritis. By 2030, 20 percent of Americans - about 72 million people - will have passed their 65th birthday and will be at high risk for the disease.
The study was also supported by the National Institute of Biomedical Imaging and Bioengineering at the NIH and a United Negro College Fund - Merck graduate dissertation fellowship.
The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the Department of Health and Human Services' National Institutes of Health, 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 NIAMS, call the information clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS Web site at http://www.niams.nih.gov .
Shamji MF, et al . Development and characterization of a fusion protein between thermally responsive elastin-like polypeptide and interleukin-1 receptor antagonist: sustained release of a local antiinflammatory therapeutic. Arthritis and Rheumatism 2007 Nov; 56 (11):3650-3661.
Betre H, et al. A thermally responsive biopolymer for intra-articular drug delivery. J Control Release. 2006 Oct 10; 115(2): 175-182.