Alpha-Melanocyte Stimulating Hormone (alpha945-MSH) Therapeutic Intervention for Prevention and Reversal of Corneal Edema Following Ocular Injury
Abstract
Objectives and Rationale of Project: Corneal endothelial cells (CEnC) have minimal regenerative capacity, and severe mechanical (penetrating or blunt-force) or chemical insults to the eye can cause significant damage to the endothelium, the inside layer of the cornea that is absolutely critical for preventing corneal swelling (edema). Indeed, severe injuries can lead to persistent corneal edema with loss of corneal clarity and thus functional vision. Damage to CEnC is often overlooked in the setting of ocular injuries and only manifests once endothelial density has already dropped below a critical threshold needed for normal vision. Indeed, there is a critical window between ocular injury and onset of endothelial decompensation in which therapeutic strategies can delay or prevent irreparable damage to vision. Currently, the only definitive therapeutic option for restoring endothelial function is corneal transplantation, which is often considered high risk in post-injury eyes. Therefore, strategies to restore endothelial function have the potential to truly transform the management of ocular injuries in addition to a myriad of other conditions that can also lead to endothelial cell damage. Current therapies, including corticosteroids and nonsteroidal anti-inflammatory topical have (1) transient and limited efficacy; (2) carry a risk of delayed wound healing and corneal melting; and (3) can actually increase the risk of CEnC death. Importantly, there is currently no treatment for reversing loss of corneal endothelial function. How the Proposal Addresses an Area of High Unmet Need: Based on the published evidence and our extensive preliminary data, we propose that alpha-Melanocyte Stimulating Hormone (a-MSH), a molecule that is constitutively expressed in the eye, can be delivered to the traumatized eye to prevent and even reverse the loss of endothelial cell function and thereby restore corneal clarity in eyes with swollen corneas. Indeed, the ability to induce immune quiescence and provide protection against cell death are critical for preventing ongoing CEnC loss after severe injuries. a-MSH is the only known molecule that appears to have the dual property of being (i) pro-regenerative while also possessing (ii) direct anti-death (cytoprotective) function and an indirect ability to protect cells through its immunomodulatory actions, thereby uniquely able to promote CEnC health and restored function. Indeed, an intriguing finding in our preliminary data is the remarkable capacity of a-MSH to prevent corneal swelling by preserving CEnC numbers even after severe types of ocular injury. Based on these preliminary data, our objectives in this grant are to use two models of mechanical and chemical corneal injury (nitrogen mustard) in order to (i) further define the mechanisms by which a-MSH so effectively prevents chronic edema; and (ii) determine whether the multiple functions of a-MSH can restore endothelial function even in eyes with chronic corneal swelling. How will this Research Advance Ocular Care and Research as it Applies to the Military and Civilian Populations? There is a clear unmet need for effective treatments for preventing CEnC loss following corneal injuries. Such a therapeutic would not only transform the outcomes of ocular injuries among both civilians and Warfighters sustaining ocular injuries but would also hold tremendous promise for preventing corneal edema and bullous keratopathy following a variety of intraocular procedures such as cataract extraction and corneal transplantation. This proposal also explores the potential of a-MSH as an effective medical countermeasure (MCM) against mustard gas keratopathy (MGK), a sight-threatening corneal condition resulting from mustard gas exposure that causes both corneal scarring and swelling. Identification of a pharmacologic intervention for restoring endothelial function would reduce the number of patients undergoing corneal transplanta
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110855
Entities
People
- Reza Dana
Organizations
- Schepens Eye Research Institute
- United States Army