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New approach for attacking lupus identified

NEW YORK CITY, Dec. 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 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 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 Hospital for Special Surgery

Founded in 1863, Hospital for Special Surgery (HSS) is a world leader in
orthopedics, rheumatology and rehabilitation. HSS is nationally ranked as No. 1
in orthopedics, No. 3 in rheumatology by U.S.News & World Report, and has
received Magnet Recognition for Excellence in Nursing Service from the American
Nurses Credentialing Center. In the 2006 edition of HealthGrades’ Hospital
Quality in America Study, HSS received five-star ratings for clinical excellence
in its specialties. A member of the NewYork-Presbyterian Healthcare System and
an affiliate of Weill Cornell Medical College, HSS provides orthopedic and
rheumatologic patient care at NewYork-Presbyterian Hospital at New York Weill
Cornell Medical Center. All Hospital for Special Surgery medical staff are on
the faculty of Weill Cornell Medical College. The hospital’s research division
is internationally recognized as a leader in the investigation of
musculoskeletal and autoimmune diseases. Hospital for Special Surgery is located
in New York City and online at www.hss.edu.

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