Interrogation of the Pathogenesis of Stiff Skin Syndrome: A Congenital Form of Scleroderma

Hal Dietz, MD
Johns Hopkins University School of Medicine
Howard Hughes Medical Institute

Project Overview

Dr. Dietz:  In broad terms, our lab has focused on the development of experimental models of scleroderma for use in exploring the events that trigger the onset and progression of tissue scarring (fibrosis). Initially we identified the gene underlying a rare inherited form of scleroderma called Stiff Skin Syndrome (SSS) and learned that manipulation of this gene in mice caused skin fibrosis through activation of a specific type of immune system cell called a plasmacytoid dendritic cell or pDC. We went on to show that manipulations that deplete pDCs or impair their function can prevent or even reverse fibrosis in SSS mouse models.

In a second series of experiments, we have been studying the basic molecular changes that are required to stimulate certain types of cells to transition to an aggressive cell type, called myofibroblasts, that drives tissue fibrosis. Importantly, we were able to implicate a specific family of enzymes (calpains), and even a specific enzyme within this family, in myofibroblast formation. Our work has shown that mice lacking this enzyme are remarkably resistant to various forms of fibrosis – pointing toward a potentially powerful treatment strategy.

Recently, we have initiated studies of skin cells from patients with systemic sclerosis (SSc) to try to understand why they remain “activated” even after removal from the body. One plausible explanation for a permanently altered cellular program in patient cells relates to the body’s ability to add stable marks to the DNA that essentially tell a given cell or cell type to ignore certain genes, but to drive other genes to produce proteins. Such marks are not inherited from our parents, but rather occur in response to various stimuli, including cellular stress and environmental cues. We are using a variety of methods to learn about the location and nature of these “epigenetic marks” that distinguish skin cells from patients with SSc from those derived from healthy controls. We are also exploring whether cells from patients with SSc can stimulate abnormal epigenetic marks when grafted onto mice. If so, this would allow the generation of a bona fide mouse model of SSc for use in treatment trials.

Research Update

Over the past year, we have been able to show that calpain inhibition can protect mice from fibrosis of many different tissues and organs, now including the lungs, skin, liver and heart. We have recently extended this work to include mouse models of human genetic diseases that include a strong predisposition for fibrosis. This work has formed the basis of a new biopharmaceutical company, called Blade Therapeutics. In partnership with Blade, we have demonstrated that a new medication has the ability to prevent a variety of forms of fibrosis in animal models, with a strong safety profile. Human studies are planned in the near future.

We have also identified specific genes that show altered epigenetic regulation in cells from patients with SSc.  We have developed both genetic and pharmacologic strategies to either inhibit problematic genes that show excessive protein production or to prevent or even reverse the underlying abnormal epigenetic marks. In the process, we are learning about the environmental cues that can stimulate the onset of fibrosis in scleroderma. Recently, we have shown that some of these treatment strategies have the ability to reverse fibrosis in skin samples obtained from patients with SSc.

How this work will impact patients

All the work in our lab is very translationally focused, meaning that we are generating and testing hypotheses that have the potential to directly improve the length and/or quality of life for people with scleroderma. This relates to the development of drug strategies (e.g. inhibitors of pDCs or myofibroblasts), identification of biomarkers (that point toward specific tissues or diseases that might be amenable to a given treatment or indicate how well a specific patient is responding to an intervention) or the creation of new and powerful experimental systems (e.g. cell culture or animal models of SSc) that can be used to develop, test or refine treatment strategies.

Role of the Scleroderma Research Foundation

In the SRF, I have found a new family of collaborators, mentors, critics (in a friendly and productive way) and partners. The annual SRF Workshop is a highlight of my professional year. My lab spends the next few months digesting and implementing new ideas and scientific approaches. The SRF has facilitated every aspect of our work, including an exciting transition from a purely academic focus to a corporate endeavor – an essential event if we hope to bring powerful new treatments to patients. SRF funding has given our lab the ability to test new and exciting ideas and to recruit extremely talented young scientists to scleroderma research.

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