Thursday, April 25, 2024
4/25/2024
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-a (PPARa) 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, PPARa 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.
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