Gene Therapy in Canine Primary Open Angle Glaucoma
Glaucoma is a progressive disease that targets a specific type of neuron in the retina called the retinal ganglion cell (RGC). The loss of these cells causes blindness. While glaucoma is associated with elevated pressure within the eye, lowering this pressure will only delay development of glaucoma. Eventually, the disease will continue to progress even though the pressure within the eye is lowered. This research project will test a new form of treatment for glaucoma that uses a novel gene therapy approach to protect retinal neurons and stop glaucoma from developing, even in the presence of elevated intraocular pressure (IOP).
This research project consists of a preclinical trial to test a novel gene therapy approach to protecting the RGCs and the optic nerve in order to stop glaucoma from progressing, even in the presence of elevated IOP.
There are two specific aims. The first objective of Aim 1 is to demonstrate that the injection of our therapeutic gene therapy vector expressing soluble FasL (sFasL) into the vitreous of the eye reaches the RGCs, and that sFasL is produced and secreted by these cells without any adverse effects. Once we show that the treatment is safe, the second objective of Aim 1 is to demonstrate that the sFasL gene therapy prevents the death of RGCs and protects the optic nerve head even when IOP is elevated. By evaluating the treated glaucoma eyes from Aim 1 in more detail, we will confirm in Aim 2 that the neuroprotective effect of sFasL gene therapy on the RGCs and the optic nerve is based on the predicted inhibition of inflammatory cells and molecular cell death pathways, while at the same time activating molecular cell survival pathways.
Gene therapy has been proven safe and effective for several inherited eye diseases in humans and animals. No such advances have been made for glaucoma, where the only treatable risk factor is lowering IOP, with which progressive vision loss often persists due to the continued loss of RGCs and degeneration of the optic nerve. Recently, we made the striking discovery that sFasL delivered to the eye by gene therapy completely stopped the loss of RGCs in two mouse models of glaucoma. As a collaborative effort between Michigan State University and Schepens Eye Research Institute, we now have the unique opportunity to perform a pre-clinical study in dogs with glaucoma, a model that mimics key elements of the human disease.
Because many eye diseases in humans and dogs are very similar, we and others have been successful in moving new gene therapies directly from dogs into human clinical trials. A significant treatment effect of the sFasL gene therapy in dogs with glaucoma would pave the way towards clinical trials of this ground-breaking therapy in human glaucoma patients.
About the Researcher
Dr. András Komáromy is a board certified veterinary ophthalmologist and vision scientist with a special interest in glaucoma. After obtaining his veterinary degree from the University of Zurich, he obtained a PhD in comparative ophthalmology and glaucomatology at the University of Florida, where he also received his clinical residency training. As a post-doctoral fellow and assistant professor at the University of Pennsylvania, he focused on the development of novel retinal gene therapies, most importantly for achromatopsia. Following his move to Michigan State University, Dr. Komáromy focused again on the study of canine glaucoma and its value as a model for a better understanding of disease mechanisms that are likewise involved in human glaucoma. The development of novel gene therapies continues to be the main interest, given their potential for effective, long-term IOP control and protection of the optic nerve. Dr. Komáromy is a recipient of the Shaffer Prize for Innovative Science (Glaucoma Research Foundation) and the Carl Camras Translational Research Award (ARVO Foundation/Pfizer Ophthalmics).
As a veterinary clinician, I am confronted daily with the challenges associated with managing different forms of glaucoma in several animal species, especially dogs. Humans and dogs represent the two species with the highest prevalence of primary glaucoma and very similar clinical signs. I frequently experience the frustration associated with the progression of optic nerve degeneration, despite aggressive medical and surgical therapies. The overarching goal of our comparative research is the identification and treatment of molecular and cellular disease mechanisms that are common in both animals and humans with glaucoma, and identifying targets for effective, mechanism-based therapies. While these therapies are mainly developed for human glaucoma patients, my personal hope is that they will also benefit our canine friends. We are immeasurably grateful to the BrightFocus donors for supporting our collaborative efforts to further develop our innovative, neuroprotective gene therapy approach to slow glaucomatous optic nerve degeneration, even with persistently elevated IOP. We hope that the results of our research projects will move us closer towards clinical trials in human patients.
My wife and I met through the veterinary profession. Together with our two sons, we share our love for animals and the exploration of nature—and having good vision makes enjoyment of these all the more rewarding.
First published on: August 28, 2017
Last modified on: June 30, 2020