Gene Therapy in Canine Primary Open Angle Glaucoma
Co-Principal InvestigatorsBruce R. Ksander, PhD Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School
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.