Monday, May 6, 2024
5/6/2024
PROJECT SUMMARY/ABSTRACT Ulcerative Colitis (UC) and Crohn’s disease (CD), the two major types of inflammatory bowel disease (IBD), are chronic diseases with recurrent symptoms and significant morbidity. There exists a lack of efficient medications for IBD, primarily due to either limited efficacy or side effects. Therefore, there is an unmet medical need to develop new effective treatments for IBD. Our compelling data using murine IBD models and human IBD patient samples demonstrated that activation of bromodomain-containing protein 4 (BRD4), an epigenetic regulator, is critical to the initiation of colonic inflammation in IBD. BRD4 inhibition reduces the inflammatory response but does not affect the anti-apoptotic response, making this strategy much safer and better tolerated (Preliminary data). Inhibition of BRD4 activation is an attractive target for the development of superior therapeutics for IBD, especially for anti-TNFa-resistant patients. We have demonstrated that BRD4 inhibition blocks the pathological activation of the BRD4 signaling, leading to the suppression of colonic inflammation in several murine models of IBD and human samples of IBD patients. Our overall objective is to develop BRD4 inhibitor-loaded nanoparticles for targeted therapy to areas of active colonic inflammation. For this purpose, we used several approaches to guide the design of colon mucosal inflammation-targeted nanoparticles. In our pilot studies, we have successfully encapsulated our new generation BRD4 inhibitors ZL0513, ZL0591, and ZL0742 into biodegradable nanoparticles using FDA-approved polymers. No apparent cell death was detected in human colonic epithelial cells (HCECs) and primary peripheral blood mononuclear cells (PBMCs) incubated with nano-encapsulated BRD4 inhibitors up to 40 µM. Also, the results of in vivo drug release tests of Nano-BRD4 inhibitors indicate their good DMPK potential. Furthermore, Nano-encapsulated BRD4 inhibitor PLGA-ZL0513 blocked the colonic inflammation at a very low dose of 1 mg/kg (p.o.) in a murine IBD model of Dextran sulfate sodium (DSS)-induced colitis. We hypothesize that local delivery of nanoparticle-encapsulated BRD4 inhibitors targeted to areas of active colonic inflammation will offer superior pharmacotherapy for IBD with higher efficacy, specific delivery, long-lasting release, and a safer therapeutic window. In this project, we will pursue the following two Specific Aims: Inspired by our compelling pilot data, we will compare the in vivo efficacy of nano-encapsulated BRD4 inhibitors with that of their non-encapsulated form on chronic colonic inflammation in murine models that mimic epithelial injury (DSS-induced colitis) and immunopathogenesis of IBD (both OXA-induced and Cbir1 T cell transfer chronic colitis) (Aim 1). We will evaluate the in vitro cytotoxicity of nano-encapsulated BRD4 inhibitors in multiple cell lines and their in vivo acute and chronic toxicity for safety studies in animals. The DMPK profile improvement (e.g., oral bioavailability and safety) by drug delivery with nanoparticles will also be examined (Aim 2). The proposed studies will lay a solid foundation as the first step in developing a first-in-class orally effective nano-medication by targeting BRD4 inhibition to improve the treatment of patients with IBD.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
