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Olivier Defert, Glenwood G Gum, Karolien Castermans, Steve Pakola, Matthew Lyulkin, Vatsala Naageshwaran, Jean-Marie Stassen; Locally-acting ROCK Inhibitor AMA0076 Improves Corneal Wound Healing in Rabbit Ethanol/Mechanical Corneal Epithelial Debridement Model. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):5610.
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© ARVO (1962-2015); The Authors (2016-present)
Rho kinase (ROCK) inhibitors have demonstrated pleiotropic effects including modulation of inflammation, fibrosis, and angiogenesis, and based on these effects constitute a pharmacologic class of potential drugs to treat both ocular and non-ocular diseases. ROCK inhibitors evaluated in the clinic for topical treatment of ocular disease so far cause unwanted hyperemia due to smooth muscle cell relaxation in conjunctival blood vessels. AMA0076 is a locally-acting ROCK inhibitor that has demonstrated pharmacodynamic effects after topical ocular administration in humans without significant hyperemia. This molecule is therefore being evaluated in preclinical models of corneal disease.<br /> The purpose of this study is to evaluate the safety, tolerability and efficacy of AMA0076 in an established rabbit corneal wound-healing model.
Standard corneal epithelial defects were created 15 anesthetized New Zealand White rabbits with alcohol application and mechanical scraping comparable to that used for photorefractive keratectomy (PRK). Animals were then randomized to receive placebo (TID), AMA0076 (TID) or positive control Genotropin (rhGH) (QID) for up to 4 days. Animals were assessed in a masked fashion by the following examinations: body weight, routine general health observation, and clinical ocular examination (slit-lamp biomicroscopy, indirect ophthalmoscopy, fluorescein staining and photography). The examinations utilized the McDonald-Shadduck scoring system.
AMA0076 was safe and generally well tolerated in rabbits with corneal epithelial defects induced by ethanol/mechanical debridement. Further, AMA0076 TID administration led to a faster rate of re-epithelialization as well as faster resolution of corneal haze than placebo. The faster resolution of corneal haze compared to placebo was similar to that achieved by rhGH, while the improved rate of re-epithelialization was greater at several time points than that achieved by rhGH.
AMA0076 was well tolerated and demonstrated an improved rate of wound healing in the rabbit ethanol/mechanical debridement model compared to placebo and the standard positive control for this model. Therefore, AMA0076 may represent a novel treatment for ocular conditions involving corneal epithelial defects.
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