A Gene Expression Map of Scleroderma

Michael L. Whitfield, PhD
Dartmouth Medical School

Project Summary:

Scleroderma is a disease with a heterogeneous presentation including changes in internal organ systems, blood vessels and skin. Quantitatively characterizing the disease with current clinical measures has proven difficult, which has made comparison of patient populations and the tracking of disease progression challenging. High throughput gene expression measured by DNA microarray or new sequencing technologies, measures the expression of every gene in the genome in a single experiment and provides a method to quantify, at a molecular level, the complex physical manifestations of scleroderma. Dr. Whitfield has used these measurements to identify patient subgroups that reflect recognized clinical classifications, such as the distinction between limited and diffuse scleroderma, and to define subgroups within each of these classifications displaying evidence of distinct biological processes. Additionally, they have preliminarily identified "biomarkers" or particular gene expression signatures that may be used to predict which patients may progress to different types of internal organ involvement. The ability to identify patient subgroups will help to connect patients with the most appropriate course of treatment.

Research Update:

Dr. Whitfield's lab has found that scleroderma patients can be segregated into smaller, more homogenous groups based on gene expression and, as a result, new subcategories of the disease have been identified. This is a significant advance since it may enhance the targeting of specific subsets of patients to appropriate clinical trials and treatments. Dr. Whitfield's work also indicates that these subsets may be stable and not change as a patient's disease progresses, meaning that these groups could be defined early in disease course. 

The patient sub-setting can be performed in a quantitative manner and offers the possibility of identifying therapies that are effective against each subset. Preliminary evidence using the drug mycophenolate mofetil (MMF) finds that patients showing a clinical response map to the inflammatory subset that the Whitfield lab and their collaborators have identified, whereas the non-responders map to different subsets. Thus patient groups, as defined by gene expression, may match best to certain prototype therapies, some of which are available today.

In order to understand the molecular basis of each subset, Dr. Whitfield has analyzed many of the common mouse models of scleroderma and has mapped each of those to gene expression-based subsets in patients. Dr. Whitfield has collaborated with Dr. Laurie Glimcher's lab to validate that the animal models currently being developed with SRF funding recapitulates the human disease. The murine sclGVHD (sclerodermatous graft versus host disease) model shows gene expression that closely approximates the inflammatory subset of systemic sclerosis patients. Detailed analysis has shown that blocking the IL13 pathway, or using inhibitory antibodies to CCL2, a protein regulated by IL13, can ameliorate disease in the sclGVHD mouse model and could be therapeutic targets in scleroderma.

Dr. Whitfield has extended these studies to numerous mouse models and is currently working with SRF-funded investigators to map the mouse models they are studying to different patient subsets of SSc. These include studies with Dr. Colin Jamora at UCSD and Dr. Radhika Atit at Case Western Reserve University.  In addition, Dr. Whitfield and collaborators have recently obtained funding from the NIH and Department of Defense to identify the disease causing mutation in the Tsk/2 mouse, which resembles the fibroproliferative subset of diffuse SSc.

This year, the Whitfield lab continues the study with access to a fresh cohort of patients from Northwestern University entered into a study to evaluate the use of mycophenolate mofetil (MMF) in scleroderma. In addition, Dr. Whitfield is continuing to examine longitudinal data and building his patient cohort samples with additional samples from Boston University. They are continuing to analyze existing data in detail including integration of multiple scleroderma datasets in different tissues for the identification of common, targetable pathways using both computational and experimental methods. In order to translate the subsets Dr. Whitfield finds in the lab into clinical use, he has developed gene expression diagnostics that can now be used in clinical trials.

The importance of Dr. Whitfield's work and his leadership in the field has been recognized by several large federal grants. These include NIH funding of a five year Center of Research Translation (CORT) grant for scleroderma and a Scleroderma Cores grant in conjunction with Boston University Medical Center and Northwestern's Feinberg School of Medicine. Finally, Dr. Whitfield and Celdara Medical have received a Small Business Innovative Research grant from NIH to develop novel methods for analyzing archived, paraffin embedded samples for disease subtyping.

What this project means for people with scleroderma:

The identification of novel disease subtypes, their underlying molecular defect and diagnostic biomarkers, will lead to a better understanding of scleroderma pathogenesis and improve the ability to identify therapies that can be targeted to an individual's specific disease. The result would be earlier diagnosis and treatments tailored to each disease subtype.

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