Focus Areas

CLINICAL TRIALS
AND
INTERVENTIONAL STUDIES

The primary goal for this program and all of its separate studies is to develop therapies for the treatment of PSC. Currently there are no effective therapies for PSC.

Immunomodulators and newer biologics while effective in the associated Inflammatory Bowel Disease are inexplicably ineffective in PSC. We are trying to harness new ideas and approaches to develop treatments for PSC. Our group has previously completed two pilot trials in PSC- one in vancomycin which did not demonstrate a benefit and a study of fecal microbiota transplant (FMT) which suggested a minor improvement in liver enzyme tests.

Learning from ulcerative colitis, we are repurposing existing medications in an effort to short-cut the drug development process in a desire to respond to the urgent need for effective medications. One current multi-center study is utilizing sulfasalazine to treat PSC. Supported by two retrospective series suggesting a benefit this study is ongoing at 14 sites in the United States. Mesalamine is metabolized to an inactive form in the intestinal lining and in the liver but sulfasalazine gets to the biliary tree without being metabolized.

We are shortly initiating the first dietary intervention in PSC testing two different dietary approaches. Another novel agent is being prepared to be studied this year as well.

BIOMARKER DEVELOPMENT

We are using a variety of omics and other novel approaches to uncover better biomarkers to be utilized in clinical trials to guide drug development in PSC better.

A challenge for clinical trials in PSC is that the standard endpoint for short term efficacy, an reduction in alkaline phosphatase which does not correlate well with a longer term improvement in the natural history of the disease.

Consequently, a major focus of our program is to identify biomarkers that are more reflective of an improvement of disease activity in PSC. In addition to serum markers we are also exploring novel imaging techniques as well as potential markers of response or non-response.

PATHOPHYSIOLOGY

The underlying causes of PSC remain unknown. The strongest clue we have is the strong association between PSC and IBD though the fundamental etiologies of PSC remain unknown as well. The work in the genetics of PSC has been illuminating but have not yet provided a pathway to understanding the disease.

Insights into the immunology of PSC have begun to dissect elements of the disease but further work is needed to develop a hypothesis of what initiates and perpetuates the inflammatory response characteristic of the disease. We are exploring a broad variety of potential specific hypotheses ranging from viral etiologies to potential microbial toxins which may be relevant to biliary injury.

MULTI-OMIC APPROACHES

In order to develop insights into PSC to guide drug development, we are utilizing a broad variety of cutting edge technologies to investigate the biologic derangements of this disease.

Metabolomics, cytokine expression arrays, proteomics among others are being explored to understand pathophysiology as well to identify biomarkers and potential drug targets as well. We are also using our knowledge of IBD and these multi-omics approaches used in UC and Crohn’s disease to understand the relationship between PSC and IBD as a critical step in developing a clearer hypothesis about the pathophysiology and treatment of this disease.

TISSUE AND DATA REPOSITORIES

In order to progress rapidly in these studies we are bringing together numerous centers in Boston as well as elsewhere in the US and working with collaborators abroad to acquire the tissue to drive these studies forward. The effort takes a great deal of coordinate planning, Whether bile, blood, stool, liver or other tissues, we are utilizing everything we can to develop insights into this disease.

MICROBIOME

The broad outlines of this disease suggest that it results from an interaction of the immune system, the environment and the microbiome.

While a distinct microbiome has been suggested in bile from individuals with PSC, we do not understand how the particular dysbiosis associated with the PSC leads to the disease. As a result we are trying to understand what are the functional consequences of the dysbiosis and how it causes biliary injury and immune activation. We are studying stool and bile to understand how the microbiome contributes to PSC.

If you are interested in becoming a collaborator, please contact us here.

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