MIF inhibition attenuates proliferative vitreoretinopathy pathogenesis and protects the eye in preclinical model

Abstract

Proliferative vitreoretinopathy (PVR) is the leading cause of surgical failure after rhegmatogenous retinal detachment, yet no pharmacologic treatment exists. Previously, we showed that inhibiting macrophage migration inhibitory factor (MIF)-a pleiotropic cytokine implicated in inflammation and fibrosis- protects the retinal neuron structure and function in a mouse model of retinal detachment and chick model of excitotoxic damage. In the present study, we demonstrate that inhibition of MIF provides protection from PVR both in vitro and in vivo. Vitreous samples of patients with PVR revealed markedly elevated MIF levels compared with controls. In TGFβ-cultured retinal pigment epithelial cells- an established model for in vitro PVR- MIF inhibition reduced proliferation and migration, suppressed epithelial-mesenchymal transition, and inhibited collagen contraction, key steps in PVR progression. In vivo, the clinically relevant MIF inhibitor ibudilast attenuated retinal gliosis in the retina and demonstrated a favorable safety profile in both chicks and rabbits. Most importantly, in a rabbit model of PVR, intravitreal ibudilast significantly slowed disease progression, protecting eyes from advancing to higher disease grades. These findings establish MIF as a likely target for PVR treatment and position ibudilast as a promising candidate with high translational potential.

Keywords: AV-1013; Animal models for eye disease; Eye disease; Gliosis; Ibudilast; Inflammation; MIF; MIF inhibition; PVR; Proliferative vitreoretinopathy; Rabbit model; Retina; Retinal detachment; Retinopathy; Translational medicine.