Investigation of novel therapeutic strategies for attenuating corneal fibrosis

Abstract

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Corneal fibrosis (scarring) is a significant cause of vision loss worldwide resulting from an exuberant wound healing response driven in part by the actions of transforming growth factor beta (TGF[beta]). Non-surgical interventions allowing for the safe and complete clinical resolution of corneal fibrosis are currently lacking in physician and veterinary ophthalmology. In order to address this significant clinical need, the research presented within this dissertation is focused on developing novel pharmacologic and gene therapies to mitigate corneal fibrosis in humans and companion animal species. This dissertation sought to evaluate the safety and efficacy of two unique pharmacologic agents (Pirfenidone and Fasudil) with known antifibrotic effects in non-ocular organ systems for attenuating TGF[beta]-mediated corneal fibrosis in vitro and in vivo. We also evaluated the ability of nanoparticle-mediated combination gene therapy (PEI-GNP) with bone morphogenetic protein 7 (BMP7) and hepatocyte growth factor (HGF) to mitigate severe corneal fibrosis in vivo following corneal alkali injury. The results of these studies demonstrated the potential clinical utility of both Pirfenidone and Fasudil (HA1077) to mitigate mild to moderate corneal fibrosis as sole antifibrotic pharmacologic agents and for combination gene therapy with BMP7+HGF to resolve moderate to severe corneal fibrosis with a single topical application of hybrid nanoparticles following corneal injury. Additional in vivo analyses are needed to evaluate potential long-term local and systemic effects owing to treatment(s) and to optimize dose and dosing regimen in a species-specific manner. Each of these therapeutic strategies holds great promise for attenuating corneal fibrosis in human and veterinary patients in clinical settings