|Targeting Systemic Sclerosis: From Bioinformatics to Clinical Research|
|Tuesday, 09 April 2013 20:34|
Systemic sclerosis (SSc), also known as Scleroderma, is a rare autoimmune connective tissue disorder that's difficult to treat. However, thanks to new research at Dartmouth's Geisel School of Medicine and Northwestern University's Feinberg School of Medicine, doctors may be able to treat some patients more effectively.
Characterized by thickening of the skin, SSc can also cause significant complications in the joints and internal organs—particularly the esophagus, lower gastrointestinal tract, lungs, heart and kidneys. There is no cure—and the one drug commonly used to treat the disease, mycophenolate mofetile (MMF) does not work for all patients. In the absence of a biomarker to inform therapeutic medical decisions, patients are exposed to ineffective and potentially toxic medications.
In the first study of its kind in Scleroderma, Michael Whitfield, PhD, associate professor of genetics at the Geisel School of Medicine, and Monique Hinchcliff, MD, MS, assistant professor of medicine at the Feinberg School of Medicine, together have shown that gene expression signatures can accurately identify patients who will positively respond to a particular therapy.
"This is a true translational research project that has progressed from an observation in my lab here at Geisel, to an approach that can influence patient care," says Whitfield. "It's been exciting to see a basic science discovery translated into the clinic so quickly.
"We think this is a great example of the type of translational science that can occur when a team with diverse and complimentary expertise successfully work together to solve a problem," he adds.
Whitfield's and Hinchcliff's findings revealed that patients whose conditions improve with MMF therapy all share a particular gene expression.
During the clinical trial, patients who improved during MMF therapy were classified in the inflammatory gene expression subset, while patients who did not improve were classified in the normal-like or fibroproliferative gene expression subsets. This fits the initial hypothesis since MMF impairs lymphocyte proliferation. A gene expression signature was also identified—the signature was composed of genes whose expression changed significantly during MMF treatment in patients that improved, but was absent in patients that did not.
The results of these experiments suggest that analysis of gene expression in skin may allow targeted treatment in patients with SSc.
While this is a small pilot study, it represents an important step forward in approaching complex rare diseases, such as Scleroderma, where existing therapies show little or no efficacy, notes John Varga, MD, John and Nancy Hughes Professor at Northwestern University Feinberg school of Medicine, who also participated in the study.
"This work is the first to associate a molecular subtype of scleroderma with targeted treatment response, " adds Howard Chang, MD, PhD, Stanford University School of Medicine. "Only patients with a particular molecular subtype benefitted from the drug mycophenolate, and these investigators discovered the gene expression changes that it induces in Scleroderma."
If validated in a larger patient cohort—soon underway—the results will have significant impact on the way we think about the development of effective treatment strategies for patients with systemic sclerosis. Their research paper, "Molecular Signatures in Skin Associated with Clinical Improvement During Mycophenolate Treatment in Systemic Sclerosis," will be published in the Journal of Investigative Dermatology.
Source: Geisel School of Medicine (2013); Targeting Systemic Sclerosis: From bioinformatics to clinical research. Original press release can be found here.