Molecular Mechanism of Ganglion Cell Death in Glaucoma

Retinal ganglion cells constitute the innermost layer of the human retina. They transmit visual information processed by other cells in the retina directly to the brain. In glaucoma, a disease that affects 2% of individuals over 40, ganglion cells selectively die, resulting in decreases in vision and even blindness. Recent research in our and other laboratories has shown striking evidence that retinal ganglion cells die by a form of programmed cell death known as apoptosis. This discovery is potentially exciting because apoptosis is a naturally occurring phenomenon in many different cell-types that is controlled by small handful of genes. Experimentally, scientists have been able to block cells from dying by manipulating the products of these genes within cells. We have hypothesized that it may also be possible to block the death of retinal ganglion cells in glaucoma by similar genetic manipulation. Such a treatment, combined with the more conventional therapies for glaucoma (which are not directly targeted at ganglion cell survival), may significantly improve the prognosis for glaucoma patients. Our approach to test this hypothesis is first to characterize which of these genes are active in retinal ganglion cells, and determine how their expression changes in animal models of glaucoma and in cultured retinal ganglion cells. We will also look for new genes that may have a role in controlling whether or not these cells die. Our primary objective is to identify the control genes that block cell death. Once we have identified the “anti-death” control genes that are expressed in retinal ganglion cells, we will try to increase their abundance in these cells to try to block cell death. To do this, we will first clone the genes and create a “synthetic” gene that is composed of the anti-death gene and a piece of another gene that will direct high levels of expression of the new synthetic gene. The synthetic gene will then be introduced into retinal ganglion cells. Our first experiments will be to test the function of the synthetic gene to block the death of ganglion cells in culture. If these tests are successful, we will expand our experiments to introduce this gene directly into the retinal ganglion cells of animals with experimental glaucoma. These gene therapy experiments will indicate to us if this form of treatment will be a viable therapy for this disease. It is important to note that even if gene therapy is not a practical approach to the treatment of glaucoma, this study will help define the molecular mechanism of how ganglion cells die and may provide the basis for other therapies aimed at blocking cell death.