Long-acting formulations of griseofulvin for ocular neovascularization therapy

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Neovascularization in the retina or choroid of the eye is a key feature of major causes of blindness such as neovascular age-related macular degeneration and proliferative diabetic retinopathy. Anti-vascular endothelial growth factor biologics have greatly aided treatment, but resistance to therapy, side effects, frequent intravitreal injections, and high cost remain significant limitations, creating a critical need for new therapy. Previous research revealed an appealing new target for the development of such therapies: the heme synthesis enzyme ferrochelatase (FECH), which, when inhibited or genetically modified, blocks neovascularization. The approved anti-fungal drug griseofulvin is naturally metabolized in vivo to form a FECH inhibitor. Griseofulvin thus blocks angiogenesis in vitro and in retinal and choroidal neovascularization animal models, offering promise for “repurposing” this old drug for ocular neovascularization treatment. However, griseofulvin has not been optimized for ocular use. For griseofulvin to be competitive with existing therapeutic modalities, it must be made available in a long-acting formulation for intravitreal use. Preliminary data reveal that griseofulvin can be formulated into polymeric implants and polymeric microparticles, which are amenable to sustained release over at least two months and effective against laser-induced choroidal neovascularization (L-CNV) weeks after application. Given this feasibility, the long-term goal is to provide a safe and affordable alternative to existing biologic agents by developing long-acting griseofulvin systems. The hypothesis is that long-term griseofulvin delivery can prevent ocular neovascularization. The hypothesis is based on prior research supporting FECH as an effective antiangiogenic target and griseofulvin as an indirect inhibitor of FECH. Polymeric implants and particles are well- received, long-term ocular drug delivery systems. With combined expertise in formulation, drug delivery, and neovascular eye disease, and preliminary results supporting controlled griseofulvin release, the team is poised to develop long-acting griseofulvin systems as new local therapies via three specific aims: 1. To optimize release kinetics of griseofulvin-encapsulated polymeric microparticles and implants. Poly(lactic-co-glycolic acid) microparticles and hot melt extruded polymeric implants will be developed to achieve 2-12 month delivery and characterized biophysically and in vitro. 2. To evaluate griseofulvin microparticles for antiangiogenic effects. Optimized microparticle formulations will be tested for long-term drug release in vivo, toxicity, efficacy, and target engagement in the L-CNV and Vldlr-/- subretinal neovascularization mouse models. 3. To evaluate griseofulvin- releasing polymeric implants for antiangiogenic effects. The optimized implant formulation will be tested for long- term drug release in vivo, toxicity, and efficacy in the DL-aminoadipic acid rabbit retinal neovascularization model. The core innovation of this strategy is the repurposing of griseofulvin for ocular neovascularization therapy by creation of sustained release formulations. If successful, these formulations would inhibit the progression of neovascularization with minimum inconvenience to the patients and cost to the healthcare system.