The Annexin A2 Pathway in Proliferative Vitreoretinopathy: A New Therapeutic Target
Abstract
Proliferative vitreoretinopathy (PVR) is a potentially blinding disease that occurs in almost one-half of military personnel who sustain a penetrating wound to the eye. It also occurs in some patients who have had complicated eye surgeries. When there is a tear in the retina (the eye s fragile, light-detecting lining), cells inside the eye that normally remain behind the retina (RPE cells) begin to proliferate, move away from their normal position, and migrate to the inner surface of the retina. Over time, these migratory cells form a scar-like membrane that pulls the remaining retina away from the back of the eye, severely compromising vision. PVR is increasing in frequency among military personnel due to the increasing use of explosive devices in modern combat. Unfortunately, however, there is no treatment for this devastating disease. Our overall objective of this program is to develop a treatment for human PVR by testing the efficacy and safety of two newly developed antibodies in two animal models. We have determined that a protein called annexin A2 allows RPE cells to abandon their normal position and migrate to the surface of the retina in response to injury. This healing-response-gone-wrong leads to the formation of damaging scar tissue. We showed previously, however, that mice completely lacking annexin A2, a protein known to enable the migration of normally stationary cells, are resistant to experimental PVR; mice lacking A2 had an over 90% reduction in damage to the eye. In addition, our early results indicate that antibodies directed against A2 can prevent PVR in mice. Therefore, we would like to determine whether blockade of A2 with two newly developed, even higher affinity antibodies can prevent PVR in two animal models. Our specific aims are to, (1) demonstrate the ability of the new A2 antibodies to prevent PVR in standard mouse and rabbit models; (2) confirm that signaling molecules called macrophage inflammatory protein-1alpha and macrophage inflammatory protein-1beta are involved in the development of PVR in mice; and (3) define how well the body distributes and metabolizes anti-A2 antibodies, and whether they are safe to use in the eye and do not harm tissues outside the eye in rabbits. If anti-annexin A2 antibodies are effective and safe in these studies, we can then recruit an industrial partner to help conduct subsequent studies that would enable us to submit an application for Investigational New Drug (IND) status. Ultimately, this work could lead to a treatment to prevent PVR that could be given to military personnel or civilians shortly after injury, while arrangements for definitive surgical repair are being made. If all goes well, we predict that anti-A2 could be tested in human subjects within several years of completing this project. This pathway could lead to treatment that prevents development of PVR altogether, thereby eliminating the expensive and disheartening short- and long-term disability that it causes.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110390
Entities
People
- Katherine A Hajjar
Organizations
- United States Army
- Weill Cornell Medicine