Saving Sight in Retinal Disease

Macular degeneration, retinitis pigmentosa, retinal detachment, optic neuropathies (such as glaucoma), and many other eye diseases cause significant vision loss in tens of millions of people worldwide. These diseases are all characterized by degenerative neural cell loss that leads to functional visual decline. While therapies exist for some eye diseases, no approach effectively interferes with this neural degeneration. Although advances have been made in our understanding of the role of apoptosis and its regulation in the pathophysiology of these diseases, neuroprotection strategies based on this knowledge have failed in clinical trials. This is likely due to the existence of unrecognized redundant pathways of cell death. One such pathway is necrosis, which was previously thought to be unregulated, but which has been recently been shown to be programmed and regulated like apoptosis in certain tissues.

Utilizing multiple in vitro and in vivo animal models of photoreceptor, retinal pigment epithelium (RPE), and retinal ganglion cell (RGC) injury and degeneration, we have shown that both caspase-mediated apoptosis and receptor interacting protein (RIP) kinase-mediated necrosis occurs to cause neural cell death. We have also confirmed expression of RIP kinases in human retinal specimens from eyes with macular degeneration. When caspases are effectively inhibited in these animal models, there is a shift from apoptosis to RIP-mediated necrosis and no decrease in neural cell loss overall, demonstrated by electron microscopy or biochemical methods. Thus, simultaneous inhibition of RIP kinases and caspases by exogenous delivery of inhibitors, or genetic deletion techniques, is essential for effective neuroprotection. In a model of retinal degeneration similar to retinitis pigmentosa, where rod photoreceptors harboring mutations die, followed by death of apparently normal cone photoreceptors, we have demonstrated that the two cell death pathways of apoptosis and regulated necrosis are synchronously modulated. The identification of these cell death pathways in multiple animal models, and their effective inhibition, provides the basis for novel combinatorial therapies for multiple retinal disorders, including age-related macular degeneration, retinal detachment, retinal degeneration, and glaucoma.