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Principal Investigator: Erik Rytting
Organization: UNIVERSITY OF TEXAS MED BR GALVESTON
Fiscal Year: 2024
Award: $237,920
Funding agency: National Institute of Allergy and Infectious Diseases
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-TNFα-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.
Terms: <(TNF)-α><Acute><Adherens Junction><Adhering Junction><Adhesive Junction><Anchoring Junction><Animal Disease Models><Animals><Apoptotic><Area><Area Under Curve><BET bromodomain inhibitor><BET inhibitor><BETi><Binding><Bioavailability><Biological Availability><Body Tissues><Bromodomain><Bromodomain and Extra-Terminal motif inhibitor><Bromodomains and extra-terminal domain inhibitor><Cachectin><Cell Body><Cell Communication and Signaling><Cell Death><Cell Line><Cell Signaling><CellLine><Cells><Cellular biology><Chronic><Chronic Disease><Chronic Illness><Colitis><Colitis associated colon cancer><Colitis associated colorectal cancer><Colitis induced colorectal cancer><Colon><Colonic inflammation><Confocal Microscopy><Crohn disease><Crohn's><Crohn's disease><Crohn's disorder><DNA Molecular Biology><DSS colitis><DSS model><DSS mouse model><DSS-induced acute colitis><DSS-induced colitis><Data><Development><Disease><Disorder><Dose><Drug Delivery><Drug Delivery Systems><Drug Kinetics><Drug Therapy><Drugs><Encapsulated><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Epithelial Cells><Epithelium><Evaluation><FDA approved><Fibroblasts><Foundations><Generations><Genes><Goals><Granulomatous Enteritis><Half-Life><Harvest><Histologic><Histologically><Histology><Human><Immune><Immunes><Immunoblotting><In Vitro><Incubated><Inflammation><Inflammatory><Inflammatory Bowel Diseases><Inflammatory Bowel Disorder><Inflammatory Response><Intracellular Communication and Signaling><Investigation><Knowledge><Legal patent><Life><Lymph Node Reticuloendothelial System><Lymph node proper><Lymphatic nodes><Lytotoxicity><Macrophage><Macrophage-Derived TNF><Measurement><Measures><Medical><Medication><Medicinal Chemistry><Mesenchymal><Mice><Mice Mammals><Mission><Modeling><Modern Man><Molecular Biology><Molecular Interaction><Monocyte-Derived TNF><Morbidity><Morbidity - disease rate><Mucosa><Mucosal Inflammation><Mucosal Tissue><Mucositis><Mucous Membrane><Murine><Mus><Mφ><NIH><National Institutes of Health><Occluding Junctions><Oral><Oral Administration><Oral Drug Administration><Outcome><PBMC><Patents><Pathologic><Patients><Peripheral Blood Mononuclear Cell><Permeability><Pharmaceutic Chemistry><Pharmaceutical Chemistry><Pharmaceutical Preparations><Pharmacokinetics><Pharmacology><Pharmacotherapy><Physiologic Availability><Pilot Projects><Polymers><Proteins><Public Health><Quantitative RTPCR><Quantitative Reverse Transcriptase PCR><R-Series Research Projects><R01 Mechanism><R01 Program><Recurrence><Recurrent><Research Grants><Research Project Grants><Research Projects><Resistance><Safety><Sampling><Sentinel><Signal Transduction><Signal Transduction Systems><Signaling><Site><Solid><Strains Cell Lines><Symptoms><T-Cells><T-Lymphocyte><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Teff cell><Testing><Therapeutic><Tight Junctions><Tissues><Toxic effect><Toxicities><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Ulcerated Colitis><Ulcerative Colitis><United States National Institutes of Health><Western Blotting><Western Immunoblotting><Zonula Occludens><biological signal transduction><bromodomain extra-terminal inhibitor><burden of disease><burden of illness><cell biology><chronic disorder><colitis induced colon cancer><colitis-induced dysbiosis><cultured cell line><cytotoxic><cytotoxicity><design><designing><developmental><dextran sulfate sodium colitis><dextran sulfate sodium induced colitis><dextran sulfate sodium model><dextran sulfate sodium mouse model><disease burden><disease model><disorder model><drug development><drug treatment><drug/agent><effective therapy><effective treatment><effector T cell><eleocolitis><epigenetically><epithelial injury><improved><in vivo><inflamed colon><inflammatory disease of the intestine><inflammatory disorder of the intestine><inhibitor><intestinal autoinflammation><intraoral drug delivery><lymph gland><lymph nodes><lymphnodes><mouse model><multidisciplinary><murine model><nano><nano formulation><nano medicinal><nano medicine><nano particle><nano particle delivery><nano toxicity><nano-sized particle><nanoencapsulated><nanoencapsulation><nanoformulation><nanomedicinal><nanomedicine><nanoparticle><nanoparticle delivered><nanoparticle delivery><nanosized particle><nanotoxicity><necrocytosis><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><parenteral administration><parenteral delivery><parenteral infusion><pilot study><polymer><polymeric><promoter><promotor><protein blotting><qRTPCR><regional enteritis><resistant><response><safety study><side effect><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><thymus derived lymphocyte>