Long-acting fenofibrate-loaded microparticles for treating retinal disorders.

Area of Science:

• Ophthalmology
• Pharmacology
• Biomaterials Science

Background:

• Age-related macular degeneration (AMD) and diabetic retinopathy (DR) are leading causes of vision loss.
• Current anti-VEGF therapies require frequent intravitreal injections and have limited efficacy in a significant patient subset.
• There is a critical need for alternative, non-VEGF therapies with sustained action for retinal disorders.

Purpose of the Study:

• To develop and evaluate fenofibrate-loaded biodegradable microparticles (Feno-MP) for long-acting intraocular delivery.
• To investigate the therapeutic efficacy of a single intravitreal injection of Feno-MP in preclinical models of DR and AMD.
• To explore a non-VEGF, PPARα-dependent therapeutic strategy for retinal diseases.

Main Methods:

• Formulation of large-sized fenofibrate-loaded biodegradable microparticles (Feno-MP) with high drug loading and sustained in vitro release (>6 months).
• Intravitreal injection (IVT) of Feno-MP into streptozotocin (STZ)-induced diabetic rats (DR model), Vldlr-/- mice (wet AMD model), and Abca4-/-/Rdh8-/- mice (dry AMD model).
• Assessment of therapeutic effects over 6 months, including electroretinogram (ERG) responses, leukostasis, blood-retinal barrier function, neovascularization, vascular leakage, photoreceptor survival, and mitochondrial function.

Main Results:

• Feno-MP demonstrated sustained retinal drug levels for at least 6 months post-single IVT in rodent models without obvious toxicity.
• In the DR model, Feno-MP restored ERG responses, decreased leukostasis, and enhanced blood-retinal barrier function.
• In wet AMD models, Feno-MP reduced neovascularization and vascular leakage; in dry AMD models, it preserved photoreceptors and improved mitochondrial function.

Conclusions:

• A single intravitreal injection of Feno-MP provides broad, sustained therapeutic benefits for diabetic retinopathy, wet AMD, and dry AMD models.
• Repurposing oral fenofibrate into a long-acting intraocular delivery system via microparticles offers a promising new therapeutic avenue.
• Feno-MP has the potential to reduce treatment burden to 1-2 intravitreal injections per year for patients with these retinal conditions.