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Sustained release of fenofibrate for the treatment of diabetic retinopathy

非诺贝特缓释剂治疗糖尿病视网膜病变

基本信息

批准号：
10684823
负责人：
Jian-Xing Ma
金额：
$ 53.8万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10684823
关键词：
Acute Address Agonist Animal Model Animals Blindness Blood Vessels Bolus Infusion Chronic Chronic Disease Clinical Clinical Research Clinical Treatment Clinical Trials Data Development Diabetic Retinopathy Dose Drug Delivery Systems Drug Kinetics Drug Targeting Dyslipidemias Endophthalmitis Extravasation Eye Fenofibrate Formulation Future Genes Half-Life Healthcare Systems Human In Vitro Inflammation Injections Insulin-Dependent Diabetes Mellitus Intercellular adhesion molecule 1 Interleukin-6 Ischemia Kidney Failure Knock-out Lead Leukostasis Lipids Maximum Tolerated Dose Medical Methods Mitochondria Modeling Monitor Morphology Non-Insulin-Dependent Diabetes Mellitus Oral Oral Administration Oryctolagus cuniculus PPAR alpha Particle Size Pathway interactions Patient Care Patients Pharmaceutical Preparations Pharmacotherapy Prevention Rattus Regulation Reporting Reproducibility Retina Retinal Neovascularization Risk Safety Streptozocin Testing Therapeutic Effect Toxic effect Treatment Efficacy Type 2 diabetic Vascular Endothelial Growth Factors Virulence Factors Vision absorption aging population angiogenesis clinical practice clinical translation compliance behavior cost db/db mouse diabetic diabetic patient diabetic rat drug standard efficacy testing improved in vivo inhibitor interest intravitreal injection lipid metabolism macular edema meter nanoparticle neovascularization new therapeutic target novel therapeutics oxidation particle preclinical development proliferative diabetic retinopathy randomized placebo-controlled clinical trial retinal toxicity safety study side effect

项目摘要

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.

项目总结