Document text
Principal Investigator: Jian-Xing Jay Ma
Organization: VIRGINIA COMMONWEALTH UNIVERSITY
Fiscal Year: 2024
Award: $538,028
Funding agency: National Eye Institute
PROJECT SUMMARY
Diabetic retinopathy (DR) is the most common cause of severe vision loss in the working-age
population in the world. However, clinical studies have shown that approximately 40% DR patients do not
adequately respond to anti-VEGF drugs. There is no drug treatment for those 40% DR patients. Furthermore,
repeated bolus injections of these anti-VEGF agents are associated with risks of injection-associated side
effects, and are a big burden to patients and the healthcare system. Fenofibrate, a peroxisome proliferator-
activated receptor-α (PPARα) agonist, is the first low-cost and safe oral drug for DR with clinically proven
efficacy against retinal neovascularization and diabetic macular edema in diabetic patients. However, oral
fenofibrate has a short half-life and poor retinal absorption. An ocular fenofibrate delivery is needed for the
treatment of DR. Intravitreal injection (IVT) of fenofibrate free drug demonstrated a short half-life of the drug in
the eye, and frequent IVT injections of fenofibrate are needed to sustain the effect. We propose a new drug
delivery strategy for providing sustained intraocular fenofibrate to target a non-VEGF, PPARα pathway and
reducing the treatment burden from DR patients. Recently, we developed small-sized 200nm biodegradable
nanoparticles containing 6% fenofibrate (Feno-NP) that demonstrated drug release for at least 8 weeks in the
eye following an IVT injection, and have no detectable ocular toxicities. Our preliminary results further
demonstrated that a single IVT injection of Feno-NP was effective on DR in the streptozotocin (STZ)-induced
T1D rat model for 8 weeks. Here, our aim is to develop and optimize new longer-lasting large-sized fenofibrate-
loaded microparticles (Feno-MP) that have higher drug loadings (≥20%) with dense PEG coating, and can
safely and effectively treat DR, for ≥ 6 months with a single IVT injection. If successful, this approach would
significantly improve DR patient care. In Aim 1, we will optimize and characterize reproducible large-sized
Feno-MP formulations that release fenofibrate for ≥6 months, determine the maximum tolerated dose, and
assess ocular pharmacokinetics (PK). The two most promising Feno-MP formulations will then be tested for
dose dependent efficacy on retinal vascular leakage and inflammation in STZ-induced diabetic rats (T1D
model) and db/db mice (T2D model) in Aim 2. Finally, we will carry out detailed safety and ocular PK studies of
one lead Feno-MP formulation in rabbits in Aim 3 to facilitate future development and potential clinical
translation.
Terms: <Acute><Address><Adult-Onset Diabetes Mellitus><Age><Agonist><Animal Model><Animal Models and Related Studies><Animals><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><BCDF><BSF-2><BSF2><Blindness><Blood Vessels><Bolus><Bolus Infusion><Brittle Diabetes Mellitus><CD54 Antigens><Chronic><Chronic Disease><Chronic Illness><Clinical><Clinical Research><Clinical Study><Clinical Treatment><Clinical Trials><Common Rat Strains><Data><Development><Diabetic Retinopathy><Domestic Rabbit><Dose><Drug Delivery><Drug Delivery Systems><Drug Kinetics><Drug Targeting><Drug Therapy><Drugs><Dyslipidemias><Endophthalmitis><Extravasation><Eye><Eyeball><Fenofibrate><Formulation><Future><Genes><HPGF><Half-Life><Health Care Systems><Healthcare Systems><Hepatocyte-Stimulating Factor><Human><Hybridoma Growth Factor><ICAM-1><IDDM><IFN-beta 2><IFNB2><IL-6><IL6 Protein><In Vitro><Inflammation><Injections><Insulin-Dependent Diabetes Mellitus><Intercellular adhesion molecule 1><Interleukin-6><Ischemia><Juvenile-Onset Diabetes Mellitus><Ketosis-Prone Diabetes Mellitus><Ketosis-Resistant Diabetes Mellitus><Kidney Failure><Kidney Insufficiency><Knock-out><Knockout><Lead><Leakage><Leukostasis><Leukostasis Syndrome><Lipids><MGI-2><Maturity-Onset Diabetes Mellitus><Maximal Tolerated Dose><Maximally Tolerated Dose><Maximum Tolerated Dose><Medical><Medication><Methods><Mitochondria><Modeling><Modern Man><Monitor><Morphology><Myeloid Differentiation-Inducing Protein><NIDDM><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Ophthalmia><Oral><Oral Administration><Oral Drug Administration><Oryctolagus cuniculus><PPAR alpha><PPAR-α><PPARalpha><PPARα><Particle Size><Pathogenicity Factors><Pathway interactions><Patient Care><Patient Care Delivery><Patient Compliance><Patients><Pb element><Peroxisome Proliferator-Activated Receptor alpha><Peroxisome Proliferator-Activated Receptor α><Pharmaceutical Preparations><Pharmacokinetics><Pharmacotherapy><Phenofibrate><Plasmacytoma Growth Factor><Population><Prevention><Procetofen><Procetofene><Rabbits><Rabbits Mammals><Rat><Rat model of diabetes><Rats Mammals><Rattus><Regulation><Renal Failure><Renal Insufficiency><Reporting><Reproducibility><Retina><Retinal Neovascularization><Risk><STZ><Safety><Sight><Slow-Onset Diabetes Mellitus><Spillage><Stable Diabetes Mellitus><Streptozocin><Streptozotocin><Sudden-Onset Diabetes Mellitus><T1 DM><T1 diabetes><T1D><T1DM><T2 DM><T2D><T2DM><Testing><Therapeutic Effect><Toxic effect><Toxicities><Treatment Efficacy><Tricor><Type 1 Diabetes Mellitus><Type 1 diabetes><Type 2 Diabetes Mellitus><Type 2 diabetes><Type 2 diabetic><Type I Diabetes Mellitus><Type II Diabetes Mellitus><Type II diabetes><Type II diabetic><VEGF><VEGFs><Vascular Endothelial Growth Factors><Virulence Factors><Vision><Zanosar><absorption><adult onset diabetes><ages><angiogenesis><care for patients><care of patients><caring for patients><chronic disorder><clinical practice><clinical translation><clinically translatable><cost><db/db mouse><developmental><diabetic><diabetic patient><diabetic rat><diabetic rat model><drug standard><drug treatment><drug/agent><efficacy testing><eye toxicity><fat metabolism><heavy metal Pb><heavy metal lead><improved><in vivo><inhibitor><insulin dependent diabetes><insulin dependent type 1><interest><interferon beta 2><intervention efficacy><intraoral drug delivery><intravitreal injection><juvenile diabetes><juvenile diabetes mellitus><ketosis prone diabetes><ketosis resistant diabetes><lipid metabolism><macular edema><maturity onset diabetes><meter><mitochondrial><model of animal><nano particle><nano-sized particle><nanoparticle><nanosized particle><neovascularization><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation therapeutics><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><ocular toxicity><oxidation><particle><pathway><patient adherence><patient cooperation><pre-clinical development><preclinical development><proliferative diabetic retinopathy><randomized placebo-controlled clinical trial><retinal toxicity><safety study><side effect><therapeutic efficacy><therapy efficacy><trial regimen><trial treatment><type 2 DM><type I diabetes><type II DM><type one diabetes><type two diabetes><vascular><vision loss><visual function><visual loss>