NEW YORK, N.Y.—December 16, 2007
Investigators at Hospital for Special Surgery have identified two new targets for drugs aimed at controlling lupus. If companies are able to develop drugs that hone in on these targets, patients may be able to control their disease with few side effects.
“The study identifies very good therapeutic targets, and what needs to be done is to identify better candidate drugs,” said Lionel Ivashkiv, M.D., director of Basic Research at Hospital for Special Surgery in New York City. He led the study, which was published online in Nature Immunology on December 16 and will appear in print in February.
Because abnormally high levels of interferon-alpha (IFN-∝) can lead to lupus, researchers have developed drugs that block interferon. These drugs, however, have immunosuppressive side effects that can leave patients vulnerable to various illnesses and infections, some of which can be deadly. Currently, these drugs are being tested in clinical trials. If researchers are able to develop drugs for the newly identified drug targets, patients may be able to avoid these immunosuppressive effects.
Interferons have two major functions. First, they protect against viruses and second, they regulate immune responses, strengthening immune responses and playing a role in autoimmunity. Different proteins, called STATs, mediate the two functions of IFN. STAT1 mediates the autoimmune and inflammatory functions, and STAT2 mediates the virus protection function. “What we were interested in understanding is how you can regulate the balance between activating the inflammatory effects and the antiviral effects,” Dr. Ivashkiv said. “We thought if we could control the functions of the interferons, that would lead to new therapeutic approaches where you could block specifically some of their functions, but not others.”
The investigators discovered that calcium specifically increases activation of STAT1 by interferons, and thus turned their attention to calcium. The researchers tested whether two kinase enzymes in the calcium-signaling pathway, CAMK and Pyk2, could be manipulated to control STAT1. In studies involving mice, the investigators showed that blocking these calcium-signaling pathways with a drug called KN-93 regulated the amount of STAT1, but not STAT2 activation.
“What we found was that these kinases that are regulated by calcium actually regulate the strength of activation of STAT1 by the interferons, but they do not regulate the strength of activation of STAT2,” said Dr. Ivashkiv. “The idea was, if you block these signaling pathways, would you block the STAT1 part, which controls the inflammatory/deleterious effects, and preserve the antiviral part? We tested that in an animal model of lupus and we were able to show, in vivo, that you can suppress STAT1 activation by inhibiting the calcium-dependent kinases.”
The researchers say that their work has identified a new therapeutic approach for attacking lupus. “What the companies are trying to develop are, basically, antibodies against the interferons. The concern there is that if you block the interferon completely, patients may become very immunosuppressed and unable to handle viral infections,” Dr. Ivashkiv said. “Our idea is that if you block these calcium pathways, you could block the deleterious effects of the interferon, but maintain the antiviral effects.”
Lupus is an autoimmune disease that can affect various parts of the body, including the skin, joints, heart, lungs, blood, kidneys and brain. Inflammation, considered the primary feature of lupus, is characterized by pain, heat, redness, swelling and loss of function. In most people, the disease affects only a few organs and symptoms are mild, but in others, the disease can cause serious and even life-threatening problems. According to the Lupus Foundation of America, an estimated 16,000 Americans develop lupus each year.
Support for the research came from the National Institutes of Health and an Abbott Scholar Award.
About HSS | Hospital for Special Surgery
HSS is the world’s leading academic medical center focused on musculoskeletal health. At its core is Hospital for Special Surgery, nationally ranked No. 1 in orthopedics (for the eighth consecutive year) and No. 3 in rheumatology by U.S. News & World Report (2017-2018). Founded in 1863, the Hospital has one of the lowest infection rates in the country and was the first in New York State to receive Magnet Recognition for Excellence in Nursing Service from the American Nurses Credentialing Center four consecutive times. The global standard total knee replacement was developed at HSS in 1969. An affiliate of Weill Cornell Medical College, HSS has a main campus in New York City and facilities in New Jersey, Connecticut and in the Long Island and Westchester County regions of New York State. In 2017 HSS provided care to 135,000 patients and performed more than 32,000 surgical procedures. People from all 50 U.S. states and 80 countries travelled to receive care at HSS. In addition to patient care, HSS leads the field in research, innovation and education. The HSS Research Institute comprises 20 laboratories and 300 staff members focused on leading the advancement of musculoskeletal health through prevention of degeneration, tissue repair and tissue regeneration. The HSS Global Innovation Institute was formed in 2016 to realize the potential of new drugs, therapeutics and devices. The culture of innovation is accelerating at HSS as 130 new idea submissions were made to the Global Innovation Institute in 2017 (almost 3x the submissions in 2015). The HSS Education Institute is the world’s leading provider of education on the topic on musculoskeletal health, with its online learning platform offering more than 600 courses to more than 21,000 medical professional members worldwide. Through HSS Global Ventures, the institution is collaborating with medical centers and other organizations to advance the quality and value of musculoskeletal care and to make world-class HSS care more widely accessible nationally and internationally.