Photoreceptor rescue PHILIP J. LUTHERT, N.H. VICTOR CHONG Abstract death.l Secondly, there is a wave of cell death in post-mitotic photoreceptor cells when metabolic Photoreceptor cell death is the final, activity in the retina increases.2 This, together irreversible event in many blinding diseases with the high focal concentrations of including retinitis pigmentosa, age-related mitochondria in photoreceptors and the very macular disease and retinal detachment. This high blood supply to the choriocapillaris, paper examines the potential strategies for suggests that there may be little reserve in the preventing photoreceptor cell death in the energy supply to photoreceptor cells? The context of current understanding of the complex inter-relationships between rods, mechanisms of cell death. There is evidence to cones, Muller cells and retinal pigment suggest that photoreceptor cells are inherently epithelium (RPE) add to the vulnerability in that vulnerable, apoptosis is the final common failure of other cell types then leads to pathway of photoreceptor cell loss, and other secondary photoreceptor cell loss. It seems retinal cells play an important role in the possible, therefore, that photoreceptors live on a survival of rods and cones. Furthermore, the 'knife-edge' and that relatively mild insult can rationale of using neurotrophic factors as significantly increase the probability of cell therapeutic agents in retinal degeneration is death. One correlate of this is that the converse discussed in detail. Photoreceptor rescue by may also operate. That is, a therapy offering a manipulation of genes involved in apoptosis relatively modest benefit to the cell may reduce and some pharmacological agents is also the chances of cell death sufficiently to have an described. important clinical impact. This is especially likely to be the case in chronic, slowly Key words Apoptosis, Gene manipulation, progressive disorders such as retinitis Neurotrophic factors, Photoreceptor, Retinal pigmentosa. degeneration, Retinitis pigmentosa Apoptosis in photoreceptor cells The aim of this paper is to discuss potential strategies for preventing photoreceptor cell Major advances have been made in our death in the context of current concepts of the understanding of apoptosis over the last few mechanisms of cell death. As retinal years. Much of the detailed biochemistry of the transplantation and gene therapy are discussed final stages of the apoptotic cascade has been elsewhere in this issue, growth factor therapy is elucidated and apoptotic cell death (ACD) has covered in most detail. been documented in a wide range of Photoreceptor cdl death is the final, circumstances. In fact, it is now clear that ACD irreversible event in many blinding diseases occurs in virtually every cell type, if not all cells, including retinitis pigmentosa, age-related that have been studied appropriately. It is also macular disease and retinal detachment. clear that most pathological insults can provoke Particularly in chronic, progressive disease, a ACD if delivered at a dose below that expected PJ. Luthert r::!:'l modest reduction in the rate of photoreceptor to cause acute, necrotic cell death. Increasingly, N.H .V . Chong cell loss might lead to a significant prolongation there are reports of necrosis and apoptosis Institute of Ophthalmology of useful vision, and over the last few years a occurring side by side, and it is now clear that Bath Street number of developments have raised hopes that ACD is not a specific process. In line with this, London EC 1V gEL, UK clinically effective treatments may become apoptosis has been described in a wide variety Tel: +44 (0)171 608 6808 available during the next decade. of hereditary retinal degenerations,4-7 in light Fax: +44 (0)171 608 6862 e-mail: [email protected] damageS and following retinal detachment9,10 and in other types of retinal degeneration.]] Inherent vulnerability of photoreceptor cells P.l. Luthert Substantially less is known about the specific N.HV Chong The combination of several pieces of indirect upstream events leading to activation of the Moorfields Eye Hospital evidence makes it likely that photoreceptor cells apoptotic cascade. However, recent London, UK are inherently vulnerable. Firstly, it is observations demonstrating the importance of N.HVC. is supported by a remarkable how many different mutations and mitochondrial function and the high metabolic MRC Clinical Training acquired insults lead to photoreceptor cell demands of rods make it likely that loss of Fellowship Eye (1998) 12, 591-596 © 1998 Royal College of Ophthalmologists 591 calcium homeostasis, free radical damage and any other the apoptotic programme in some cell-insult process leading to mitochondrial failure may be of combinations.15.16 The appeal of interfering with the significance. It remains unclear, however, why mutations apoptotic pathway is that, given the ubiquity of in rhodopsin and other transduction proteins result in apoptosis in chronic cell death, a single therapy might be cell death. effective for a very large number of conditions. Unfortunately, therapies operating so far downstream may be acting too late to do anything other than The key role of retinal cell-cell interactions in temporarily slow disease, and in early studies this photoreceptor cell survival appears to be the case. As discussed above, photoreceptors are in close anatomical and functional relationship with their Photoreceptor rescue, retinal injury and growth factors neighbouring cells. The importance of the RPE is clear and perhaps most evident in the Royal College of An unexpected finding was observed during the early Surgeons (RCS) rat, in which failure of phagocytosis of attempts at retinal transplantation for photoreceptor rod outer segments leads to marked outer retinal rescue. Focal injury to the retina appeared to protect atrophy. Direct evidence for the significance of Muller photo receptors from degeneration. This was clearly cells is less abundant, although in a mouse with a illustrated in the RCS rat, when mechanical injury mutation of AMOG (adhesion molecule of glia)12 produced by an injection of saline into the subretinal or photoreceptor loss occurs secondary to glial failure. into the vitreous, or even insertion of a needle without Finally, photo receptors depend on each other for injection, led to protection of photoreceptors near the survival. Rod loss in diffuse retinitis pigmentosa (RP) is wound.17-19 This protection was not restricted to followed by cone loss, and in certain macular genetically determined retinal degeneration. Similar dystrophies the opposite holds true. photoreceptor rescue by mechanical injury was observed Raff focused attention on the importance of growth in the light-induced retinal damage in the rat/o although factors as intercellular mediators of cell survival.13•14 interestingly this and related strategies are less effective Most of his observations related primarily to cell in the mouse. Furthermore, this is not restricted to populations in development, but it is clear that similar photoreceptor cells, as a similar self-protective relationships exist in many adult tissues. Although there mechanism appears to exist for retinal ganglion cells.21 is little to suggest that any human photoreceptor cell These findings imply that the retina has a self-protective degeneration is primarily due to growth factor failure, mechanism that can be activated to protect, at least higher levels of growth factors have, in certain partially, photo receptors and ganglion cells from damage circumstances, the capacity to protect cells and much or death. Injury-induced photoreceptor rescue extends experimentation has addressed this mode of rescue in beyond the immediate vicinity of the lesion, suggesting photoreceptors. that soluble factors are involved.17,18,22 As mechanical injury to the eye increases the expression of basic fibroblast growth factor (bFGF) and ciliary neurotrophic Cellular targets for photoreceptor rescue factor (CNTF) in the rat retina23 it was logical to assume Even though much remains to be learnt about the that these agents might be responsible for the protection detailed pathogenesis of photoreceptor cell death, there and to explore the effects of growth factor injection on are several potential cellular targets for rescue. At the cell photoreceptor cell survival. membrane growth factor interactions with their receptors are important determinants of cell survival and these are Neurotrophic factors discussed at length below. Ion homeostasis is also critical for all neuronal cells and a small number of studies have There are at least four families of neurotrophic factors explored the capacity of calcium channel blockers to that might be important in photoreceptor rescue: protect photoreceptors. Sustained increases in the levels fibroblast growth factors such as bFGF, cytokine­ of free calcium within cells lead to the activation of associated neurotrophic factor such as CNTF, numerous potentially toxic enzyme systems and, neurotrophins such as brain-derived neurotrophic factor importantly, can be toxic to mitochondria, leading to a (BDNF) and insulin-like growth factors (IGF) such as vicious cycle of energy failure, free radical generation, IGF-I and IGF-II. further mitochondrial toxicity and loss of calcium bFGF is a member of the fibroblast growth factor homeostasis. (FGF) family, a group of heparin-binding, Single-chain An important strategy for inherited degeneration is to polypeptides about 150-300 amino