Collaborating to solve a painful mystery
Patients battling the debilitating and painful progression of scleroderma face a painful journey. The exact cause of the disease is not yet clearly understood, and there are few good treatment options - let alone a cure – for it. Yet although we have a long way to go to defeat scleroderma, survival rates continue to improve as research advances lead to better treatments for the specific internal organ complications it causes. Many of those breakthroughs are being made in the labs and clinics of the University of Michigan.
Since the U-M Scleroderma Program launched in 2004, we have remained focused on our dual mission of developing more effective therapies for scleroderma and its complications while investigating the causes and mechanisms of this complex disease. That requires a multidisciplinary approach to everything we do, involving U-M faculty from disciplines including the Division of Rheumatology, the Interstitial Lung Disease Program in the Division of Pulmonary and Critical Care Medicine, the Pulmonary Hypertension Program of the Division of Cardiology, pediatric rheumatology, the Department of Dermatology, the Division of Hand Surgery, the Department of Occupational Therapy and the Cancer Center.
Clinical care is provided primarily to patients throughout Michigan and the Midwest, but the program also serves as an international referral center.
One “switch” closer to a cure
In the spring of 2014, a unique collaboration between investigators at U-M and Michigan State University published a groundbreaking study detailing both their identification of a signaling pathway that turns off scleroderma and a class of chemical compounds that can flip the switch.
“The majority of drug treatments that exist today for fibrosis basically look at reducing just the inflammation,” says Dinesh Khanna, M.D., M.S., director of the U-M Scleroderma Program. “There are other drugs that block one or two of the signaling pathways that cause the disease, but scleroderma has many of these pathways.” These new compounds target the genetic switch that controls the formation of myofibroblasts – cells that produce too much collagen, which leads to thickening of skin and damage to other organs.
The work originated in the lab of former U-M pharmacology professor Richard Neubig, M.D., Ph.D., now chair of the Department of Pharmacology and Toxicology at the MSU College of Osteopathic Medicine. “The genetic switch that controls the fibrosis process for scleroderma is one that we’ve been studying in my lab for about 10 years,” says Neubig. “But we only recently discovered new compounds that have shown initial success in blocking that switch. We have begun testing those compounds in fibroblasts from scleroderma patients, and are very enthusiastic about their potential to treat and possibly to reverse scleroderma based on the results we’ve seen so far.”
Numerous research steps must be completed before the discovery can be translated for use in human patients, but if successful, the approach may be have the potential to slow or stop the progression of other diseases besides scleroderma, including idiopathic pulmonary fibrosis and Crohn’s disease.
David Fox, M.D., chair of the U-M Division of Rheumatology, agrees that the initial efforts are promising, but cautions that it could take several years before continued success in the laboratory might translate into clinical trials. “We need to expand the cell culture studies, greatly expand the research in animal models, including looking at the ability of these compounds to target fibrosis in the lungs — the most deadly aspect of the disease — and also refine the delivery method to ensure it will be well-tolerated,” Fox says.
“A few years may sound like a long time,” he adds, “but when you’re talking about something that has the potential to dramatically improve the quality of life for hundreds of thousands of patients, it’s important to get the science right.”
The University of Michigan has filed for patent protection for the discovery and is currently looking for a licensing partner to help bring it to market.