Scientists
from the Florida campus of The Scripps Research Institute have
developed the first of a new class of highly selective compounds that
effectively suppresses the severity of multiple sclerosis in animal
models. The new compound could provide new and potentially more
effective therapeutic approaches to multiple sclerosis and other
autoimmune diseases that affect patients worldwide.
The study appeared April 17, 2011, in an advance online edition of the journal Nature.
Current
treatments for autoimmunity suppress the patient’s entire immune
system, leaving patients vulnerable to a range of adverse side effects.
Because the new compound, known as SR1001, only blocks the actions of a
specific cell type playing a significant role in autoimmunity, it
appears to avoid many of the widespread side effects of current
therapies.
“This
is a novel drug that works effectively in animal models with few side
effects,” said Tom Burris, Ph.D., a professor in the Department of
Molecular Therapeutics at Scripps Florida who led the study, which was a
multidisciplinary collaboration with scientists including Patrick
Griffin, William Roush, and Ted Kamenecka of Scripps Research, and Paul
Drew of the University of Arkansas for Medical Sciences. “We have been
involved in several discussions with both pharmaceutical and
biotechnology firms who are very interested in developing it further.”
A
lengthy process of drug development and review is required to ensure a
new drug’s safety and efficacy before it can be brought to market.
“This
impressive multidisciplinary team has used a combined structural and
functional approach to describe a class of molecules that could lead to
new medicines for treating autoimmune diseases,” said Charles Edmonds,
Ph.D. who oversees structural biology grants at the National Institutes
of Health. “Breakthroughs such as this highlight the value of scientists
with diverse expertise joining forces to solve important biological
problems that have the potential to benefit human health.”
Targeting specific receptors
For
the past several years, Burris and his colleagues have been
investigating small-molecule compounds that affect particular
disease-related receptors (structures that bind other molecules,
triggering some effect on the cell). In particular, the scientists have
been interested in a pair of “orphan nuclear receptors” (receptors with
no known natural binding partner) called ROR? and ROR? involved in both
autoimmune and metabolic diseases.
These
particular receptors play a critical role in the development of TH17
cells, a form of T helper cells that make up part of the immune system. A
relatively new discovery, TH17 cells have been implicated in the
pathology of numerous autoimmune diseases, including multiple sclerosis,
rheumatoid arthritis, inflammatory bowel disease, and lupus. TH17 cells
produce Interleukin-17, a natural molecule that can induce
inflammation, a characteristic of autoimmunity.
“If
you eliminate TH17 cell signals, you basically eliminate the disease in
animal models,” Burris said. “Our compound is the first small-molecule
orally active drug that targets this specific cell type and shuts it
down. Once SR1001 is optimized, chances are it will be far more potent
and effective.”
The compound works without affecting other types of T helper cells and without any significant metabolic impact, Burris added.
The
study was supported by the National Institutes of Health’s National
Institute of General Medical Sciences, National Institute of Diabetes
and Digestive and Kidney Diseases, and National Institute of Mental
Health.
The
first author of the study, “Inhibition of TH17 Differentiation and
Suppression of Autoimmunity by a Selective Synthetic ROR Ligand,” is
Laura A. Solt of Scripps Research. In addition to Burris, Griffin,
Roush, Kamenecka, Drew, and Solt, other authors include Naresh Kumar,
Philippe Nuhant, Yongjun Wang, Janelle L. Lauer, Jin Liu, and Monica
Istrate of Scripps Research; Dušica Vidovi?, Stephan C. Schürer of
Scripps Research and the Center for Computational Science, University of
Miami; and Jihong Xu and Gail Wagoner of the University of Arkansas for
Medical Sciences.
Filed Under: Drug Discovery
