A Gene Expression Map of Scleroderma

Michael L. Whitfield, PhD
Dartmouth Medical School

The goal of the Whitfield lab has been to understand the variability observed in scleroderma by physicians in the clinic and determine what is happening in the skin at a deep molecular level. Specifically, they work to determine which genes show changes in expression in the disease and how this influences disease progression as well as treatment strategies.

Project Summary:

SRF-funded work from my lab has allowed us to understand the patient-to-patient and disease-stage variability seen in systemic sclerosis (SSc), link this variability to disease progression and identify molecular mechanisms that results in fibrosis of the skin, internal organ dysfunction (e.g.: GI symptoms), and pulmonary problems. My lab, with SRF support, has identified “molecular fingerprints” of SSc that determine where a patient is in their disease progression and allow us identify drugs that may be useful in treating these patients. We have also linked these SSc disease states to model systems that we can use to better understand the disease. These include mouse models of disease in which we can test hypotheses, but more recently, we have developed 3-dimensional tissue models that resemble human skin. These culture models are made using SSc or healthy control skin cells and reproduce many disease features (skin thickness and fibrosis) that we observe in patients. Robust model systems allow us to test our hypotheses about how SSc progresses and what drives it—all critical parts of developing effective treatments.

A second major component of my lab is integrating the genomic data generated from my laboratory as well the vast amounts of genomic data available in the public domain, to better understand SSc pathogenesis. These analyses use bioinformatics, gene-gene networks and systems biology to understand how groups of genes act together (or against each other) in SSc patients. We have been able to use these methods to generate a molecular model of SSc pathogenesis. We have been able to further show that the molecular processes that drive skin fibrosis are likely the same processes that are driving disease in other organ systems (GI tract and lungs) of the body. We are now testing these hypotheses by analyzing data from multiple organs from single patients and asking if they show the same deregulated molecular processes. We are also performing molecular experiments in model systems to test our hypotheses. These data tell us that a common mechanism is likely driving disease across organs in SSc patients. Our goal is to target this fundamental mechanism therapeutically.

Finally, my lab is constantly working to actively translate our findings from bench to the bedside. These studies have included development of molecular measures of disease severity that can be used in clinical trials, diagnostic markers that identify a patients molecular state (i.e., which gene expression fingerprint is found in a patient), and finally, using our data to identify novel therapeutic targets and then establishing collaborative efforts to develop therapies against those targets. Our goal is to bring precision medicine efforts that are now becoming commonplace in cancer to SSc.

Research Update:

We have developed multi-tissue networks that implicate cells of the innate immune system (such as alternatively-activated macrophages and dendritic cells) that we believe are driving SSc in skin and internal organs affected by the disease. We have shown that these cells produce many of the molecules that have been implicated in driving SSc. Our network methods have also been used to perform a meta-analysis of multiple SSc clinical trials and we have been able to use these methods to predict possible combination therapies. We are performing experiments in mouse models and in our model skin-equivalents to confirm that eliminating these cells prevents fibrosis, something that has already been shown in other diseases such as kidney fibrosis. Our diagnostic assays that we have developed in-part with SRF funding help us identify the patients with these cells in the clinic. We have implemented new efforts to develop novel therapeutics that can be used to treat SSc. These include efforts to target the cells driving SSc in collaboration with academic and industry partners. In particular, we are leveraging the methods pioneered in cancer immunotherapy at Dartmouth to develop immunotherapy for patients with SSc. We will combine our diagnostic assays and therapeutic targeting to develop a precision medicine strategy in SSc.

How This Work Will Impact Patients:

Our work is providing a comprehensive molecular mechanism for SSc that will help us develop better therapies. The active translation of our work from bench to bedside means that our measures of disease severity and our diagnostic subsetting of patients are already being actively used in SSc clinical trials around the country. Our methods are helping physicians interpret the outcomes of these clinical trials and identify the patients most likely to improve on a particular treatment. Our network-based methods are now being used to analyze the molecular data derived from clinical trials; we have started to use these methods to predict combinations of drugs that may be most beneficial to SSc patients. We hope that our efforts to find new and improved therapies will ultimately benefit patients by developing drugs (or combinations of drugs) with greater efficacy.

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