Effect of ABT-263 on Intestinal Fibrosis in Human Myofibroblasts, Human Intestinal Organoids, and the Mouse Salmonella typhimurium Model.

BACKGROUND: Intestinal fibrosis and subsequent intestinal obstruction are common complications of Crohn's disease (CD). Current therapeutics combat inflammation, but no pharmacological therapy exists for fibrostenotic disease. Pathological persistence of activated intestinal myofibroblasts is a key driver of fibrosis in CD. In other organ systems, BH-3 mimetic drugs that affect Bcl-2 apoptotic pathways induce apoptosis in activated myofibroblasts and reduce fibrogenic gene expression, thereby reducing fibrosis. METHODS: We evaluated the proapoptotic and antifibrotic efficacy of several classes of BH-3 mimetics in 2 in vitro fibrogenesis models. The candidate molecule, ABT-263, was advanced to a 3-dimensional human intestinal organoid (HIO) model. Finally, the therapeutic efficacy of ABT-263 was evaluated in the mouse Salmonella typhimurium intestinal fibrosis model. RESULTS: The BH-3 mimetics induced apoptosis, repressed fibrotic protein expression, and reduced fibrogenic gene expression in normal human intestinal myofibroblasts. The BH-3 mimetics that target Bcl-2 and Bcl-xl demonstrated the greatest efficacy in vitro. The ABT-199 and ABT-263 induced apoptosis and ameliorated fibrogenesis in the in vitro myofibroblast models. In the HIO model, ABT-263 inhibited fibrogenesis and induced apoptosis. In the mouse S. typhimurium model, dose-dependent reduction in macroscopic pathology, histological inflammation, inflammatory and fibrotic gene expression, and extracellular matrix protein expression indicated ABT-263 may reduce intestinal fibrosis. CONCLUSIONS: In vitro, the antifibrotic efficacy of BH-3 mimetics identifies the Bcl-2 pathway as a druggable target and BH-3 mimetics as putative therapeutics. Reduction of inflammation and fibrosis in the mouse intestinal fibrosis model by ABT-263 indicates BH-3 mimetics as potential, novel antifibrotic therapeutics for Crohn's disease.

Intestinal fibrosis is a common complication of Crohn's disease, yet no effective therapies exist to treat fibrostenotic disease. We report ABT-263 (navitoclax) reduces intestinal fibrosis in in vitro models and reduces inflammation and fibrosis in a mouse IBD model.

Attempting Randomized Housing First Research in a Community Context: Reflections on Failure.

The Housing First (HF) model of permanent supportive housing for individuals experiencing chronic homelessness has a strong evidence base that has largely been driven by researchers in the field of community psychology in partnership with community-based organizations. However, important gaps in the HF literature remain. Implementing rigorous research designs to further the evidence for HF requires immense resources to fund both the housing intervention and the research activities. In the absence of such resources, university-community partnerships may be established to integrate research within business-as-usual services and utilize existing housing units. This first person account presents a "post-mortem" exploration of an attempt to conduct a randomized trial of scattered-site and single-site approaches to HF within a community context from the perspectives of multiple stakeholders involved in the endeavor. Despite strengths of the research collaborative, the project did not come to completion due to a series of both insurmountable and avoidable barriers. Yet, the experience illuminated several potential challenges researchers and housing providers conducting work in this area may encounter, such as ever-changing homeless service system policies that may impact research and organizational procedures. Lessons learned and recommendations for preventing or overcoming systems-level barriers and potential challenges within the university-community partnership are described.