SOURCE Scleroderma Research Foundation
SAN FRANCISCO, Oct. 9, 2013 /PRNewswire-USNewswire/ -- The Scleroderma Research Foundation today said that researchers at The Johns Hopkins University working in a novel mouse model of Stiff Skin Syndrome have made key discoveries that may have broad implications for future scleroderma therapy. In a report to be published online on October 10th in Nature, scientists show that integrin-modulating agents can arrest fibrosis in a model of scleroderma-like skin fibrosis and, more strikingly, that established fibrosis can be resolved with such agents. Although years away from an approved drug, the conclusion stands in sharp contrast to traditional thinking about scleroderma's irreversible advance and its resistance to therapeutic intervention. The Scleroderma Research Foundation has supported the work for the past six years.
Systemic sclerosis (commonly referred to as scleroderma) is a rare autoimmune disease affecting approximately 1 in 4,000 Americans. A signature symptom is fibrosis of the skin, although the disease typically affects the lungs, kidneys and other organs with life-threatening consequences. Like many complex, adult-onset autoimmune diseases, animal models replicate some, but not all features of the disease. This gap has slowed work in the scleroderma field.
In the Nature report, a group led by Hal Dietz, M.D., focused on a genetic fibrotic disease called Stiff Skin Syndrome to provide insights. Dr. Dietz is a Professor of Genetics at The Johns Hopkins University School of Medicine, Director of the William S. Smilow Center for Marfan Syndrome Research and an Investigator for the Howard Hughes Medical Institute. "We looked to Stiff Skin Syndrome, an ultra-rare form of inherited scleroderma-like skin fibrosis as a means to understand the very similar skin fibrosis of systemic sclerosis," explains Dietz. "Reasoning that if we could understand how a single point mutation in the fibrillin-1 (FBN1) protein causes skin fibrosis in Stiff Skin Syndrome (SSS), this would help us to understand the biological pathways involved in systemic sclerosis, a typically acquired, adult-onset autoimmune disease."
"There may be a final common pathway by which cells lose their normal control," postulates Dietz, "and even if one condition is genetic and the other is not, they may both funnel down to the same mechanism."
"Our creation of the SSS mouse model marked the first time we could breed large numbers of animals to see what is happening in the tissues at every step along the way-from predisposition to end-stage tissue failure," says Dietz. "There is a very fundamental process that goes awry: cells in the skin of the SSS mouse model lose the ability to attach to the extracellular matrix and to sense their surroundings. Those cells then become activated and stimulate an immune reaction that causes the surrounding cells to produce excessive amounts of collagen, resulting in fibrotic skin. What's most exciting is that we discovered a strategy to suppress abnormal immune cells. We also found that we could not only prevent but also reverse established skin fibrosis."
Treatment with specific integrin binding antibodies as well as with TGF-beta neutralizing antibodies both prevented and, in a separate experiment, resolved fibrotic skin in the SSS model. The Dietz group tested the same therapeutic strategies on cells cultured from the skin of patients with systemic sclerosis and found that the same treatments that are effective in SSS mice were able to suppress collagen production in the cells from systemic sclerosis patients. Dietz believes that "some of these treatment strategies could transition very quickly to patients as pharmaceutical companies are already exploring the targets for other conditions, including cancer."
"A key finding of this study is the unexpected discovery that fibrosis can be reversed. This is a major advance in our thinking about fibrosis. It reveals that the fibrotic process is actually quite dynamic; therefore, when a drug succeeds in preventing excessive production of collagen, existing fibrosis can be diminished," said David Botstein, Ph.D., the Anthony B. Evnin Professor of Genomics and Director of the Lewis – Sigler Institute for Integrative Genomics at Princeton University, who is also a Scientific Advisor of the Scleroderma Research Foundation. "Within eight weeks of treatment, the researchers were able to fully normalize fibrotic skin in a mouse model so that it became impossible to distinguish treated fibrotic tissue from normal tissue."
Scleroderma Research Foundation Scientific Advisor Antony Rosen, M.D., who is Director of the Division of Rheumatology at The Johns Hopkins University School of Medicine and the Mary Betty Stevens Professor of Medicine as well as a Professor of Cell Biology and Pathology added that "equally surprising is that the SSS mice have an immune response that targets the identical protein (topoisomerase I) that is targeted in systemic sclerosis. We hope that investigating that similarity-how the immune system gets stimulated and targets that molecule-will tell us a great deal about the mechanism of systemic sclerosis."
"This work really gives us hope that we have gained some fundamental insights into the process of fibrosis and, with this model, we are positioned both to determine how dysregulation of these biological processes occurs in systemic sclerosis and to rapidly and efficiently test new treatment strategies," explains Luke Evnin, Ph.D., Chairman of the Board of Directors of the Scleroderma Research Foundation and a scleroderma patient.
"Hal's expertise in genetics and connective tissue diseases, together with his phenomenal success in translating his discoveries about the action of fibrillin-1 in Marfan syndrome into therapeutic insights that directly benefit Marfan's patients inspired us to approach him and explore whether there was a productive area of overlap for us," says Evnin. Dietz adds, "I credit the Scleroderma Research Foundation with great foresight and wisdom in coming to someone with no track record in scleroderma and saying, "give us your best idea, think broadly, and see if you can help us make progress."
Additional authors on the paper included first author, Elizabeth Gerber, M.D./Ph.D. student; Elena Gallo, Ph.D.; and David Huso, D.V.M., Ph.D., among others. The project was also completed in collaboration with Fredrick Wigley, M.D., Professor of Medicine and Director of the Scleroderma Center of Excellence at Johns Hopkins, one of the premier scleroderma centers in the United States, which the Scleroderma Research Foundation has supported since its inception.
The study was funded by the Scleroderma Research Foundation, America's leading nonprofit investor in research aimed at improved therapies and a cure for patients with scleroderma, with additional support from the National Institutes of Health, the National Marfan Foundation, the Smilow Center for Marfan Syndrome Research and the Howard Hughes Medical Institute.
More about Scleroderma and the Scleroderma Research Foundation:
The word scleroderma literally means "hard skin," but the disease is much more than that, often affecting the internal organs such as the lungs, heart, kidney and gastrointestinal tract with life-threatening consequences. In some cases, the joints and muscles are affected, resulting in severe pain and limited mobility. Vascular damage due to scleroderma can result in loss of digits and entire limbs.
The symptoms and severity of scleroderma vary from one person to another and the course of the disease is often unpredictable. Women are disproportionately affected with scleroderma (representing four out of five patients), usually striking in the prime of their lives, between the ages of 20 and 50; however, children and men of all ages and across all ethnic boundaries can also be affected.
Today, there is no way to prevent scleroderma and there is no cure. Treatments are available for some but not all of the most serious complications. The continued success of the SRF is entirely dependent upon charitable gifts from individuals and corporations.
The Scleroderma Research Foundation was founded in San Francisco in 1987 by scleroderma patient Sharon Monsky who lost her battle to the disease in May of 2002. Monsky's legacy lives on through the organization she founded which is currently chaired by Luke Evnin, Ph.D., managing partner of MPM Capital, a dedicated investor in life sciences. "We continue to pursue Sharon's vision," says Evnin. "We are in business to go out of business and, thanks entirely to a growing network of thousands of supporters and generous donors, we will press forward until a cure is found."
The Foundation's collaborative approach is enabling scientists from leading institutions across the nation and around the world to work together and develop an understanding of how the disease begins, how it progresses and what can be done to slow, halt or reverse the disease process.
For more information, call (800) 441-CURE or visit www.sclerodermaRESEARCH.org.
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