RPE transplantation and its role in retinal disease
Introduction
It is now approximately 20 years since the earliest works carried out in retinal pigment epithelium (RPE) transplantation were first published (Gouras et al., 1983, Gouras et al., 1985; Li and Turner, 1988b; Lane et al., 1989). It seems timely to review these pioneering reports and the subsequent progress in this area especially in the light of the explosion of new techniques and treatments for retinal diseases that have been developed over the past decade. We will examine the potential for RPE transplantation in the treatment of retinal diseases based on the published literature. This will allow us to anticipate the part it will play relative to treatments such as gene therapy, anti-vascular endothelial growth factor (VEGF) agents (Brown et al., 2006; Rosenfeld et al., 2006; Gragoudas et al., 2004), photodynamic therapy (PDT) (Michels and Schmidt-Erfurth, 2001), angiostatic steroids (Russell et al., 2007), and the artificial retina (Terasawa et al., 2006; Zaghloul and Boahen, 2006), among the many new treatment paradigms both available and proposed.
The RPE is a neuroepithelium-derived, cellular monolayer that lies on Bruch's membrane between the photoreceptor outer-segments and the choriocapillaris. With the photoreceptor layer it constitutes a functional unit that provides the transducing interface for visual perception (Strauss, 2005). Therefore, optimal functioning of this unit is critical to sight (Custer and Bok, 1975). The RPE is also a metabolically complex and active cell layer that is important for local homeostasis and maintenance of the extraphotoreceptor matrix. The pivotal role of the RPE in respect to photoreceptor function and local cellular and extracellular homeostasis accounts for the impact on sight of any disease or abnormality that affects the layer. The functions and characteristics of the RPE have been reviewed and documented extensively (Marmour and Wolfensberger, 1998; Strauss, 2005; Bharti et al., 2006). This central importance of RPE to normal retinal structure and function explains the rationale and attraction of using RPE transplantation in the treatment of retinal diseases.
More recently, with the increased understanding of the molecular and cellular mechanisms of disease processes, most importantly inflammation and neovascularisation, the concept of healthy RPE as a therapeutic cell has emerged. In terms of angiogenesis-related factors both pigment epithelial-derived factor (PEDF) and VEGF are secreted by the RPE (Tanihara et al., 1997a; Witmer et al., 2003; Zhao et al., 2006; Cai et al., 2006). The extracellular matrix, which can have an antiangiogenic function, is also secreted by the RPE. This potential for modulation of the extracellular milieu and modulation of disease processes means that RPE transplantation can benefit in ways that are in addition to the restoration of normal anatomy and supporting function for photoreceptor needs.
Despite the complexity of the RPE cell and the number of metabolic processes that are unique to it there are relatively few pure primary RPE disorders (Marmour and Kent, 1998). Examples of specific RPE disorders are the monogenic dystrophies that include those arising from mutations in lecithin retinol acyltransferase (LRAT) (Thompson et al., 2001; Ruiz et al., 2001), RPE 65 (Veske et al., 1999; Gu et al., 1997), merTK (D’Cruz et al., 2000; Duncan et al., 2003; Tschernutter et al., 2006) or bestrophin (Sun et al., 2002; Marmorstein et al., 2000). Treatment of some of these dystrophies such as RPE 65 and the merTK dystrophies may well be achieved by gene therapy rather than cell transplantation (Acland, 2001, Acland, 2005; Pang et al., 2006; Vollrath et al., 2001; Tschernutter et al., 2005). Others however, such as Best's disease, where there is structural loss and damage to the RPE, will require repopulation of the cell layers with unaffected RPE cells. Although there are few primary RPE dystrophies there are many more photoreceptor dystrophies that lead to secondary RPE atrophy and dysfunctions. The observation of RPE atrophy in primary photoreceptor disorders shows that RPE transplantation may have a broader role than for solely RPE diseases.
Possibly more important in visual morbidity is the role of the RPE in modulation of complex disease processes such as inflammation and neo-vascularisation that are seen in age-related macular degeneration (AMD) (Nowak, 2006), diabetic retinopathy and chronic inflammatory diseases. The RPE can be involved in both the active disease such as the inflammatory response or in the balance of factors that permit neo-vascularisation (Tanihara et al., 1997b; Witmer et al., 2003; Zhao et al., 2006; Cai et al., 2006). Alternatively, the loss of RPE may be the manifestation of the degenerative aspect such as in dry AMD. As such, RPE transplantation can theoretically be used in specific well-defined photoreceptor and RPE disease as well as more global multifactorial diseases involving the outer retina and choroid. The effects may be enhanced in the future by altering the RPE cell by ex vivo gene transfer or altering the immune markers on non-autologous cells.
This review examines the literature describing RPE transplantation to date in animal and humans. With this as a background we discuss the future of RPE transplantation and its future role in the treatment of retinal diseases including the interaction with other treatment modalities.
Section snippets
RPE allograft in mice
Transgenic mice models have been used to investigate the presence and extent of immune privilege in the subretinal space. Both cell-associated and soluble antigens injected into the subretinal space can actively suppress systemic delayed-type hypersensitivity (DTH) reaction, confirmed by adoptive transfer assay of splenocytes (Wenkel and Streilein, 1998). Such immune deviation was abolished when the RPE was damaged by sodium iodate (Wenkel and Streilein, 1998). This suggests that submacular
Human RPE transplantation
Since the first case report of human homologous and autologous RPE transplantation for the treatment of exudative AMD (Peyman et al., 1991), over 30 more homologous and 230 more autologous RPE grafts have been performed (Table 2). Most of the human work has concentrated on neovascular AMD and several laboratory and clinical findings support the need for RPE grafting after excision of the subretinal neovascular membranes. The major steps in human RPE transplantation are summarised in the
Future trends in RPE transplantation
Transplantation in both animal and humans has shown the potential to restore vision and maintain function in retinal diseases. Although this is sufficient in terms of proof of principle the quality and consistency of restoration of visual function has fallen short of other techniques such as translocation or the injection of anti-VEGF agents. The ability to restore structure and function has been demonstrated but a well-defined reproducible technique and a widely accepted cell source has not
Conclusion
Following approximately 20 years of research into RPE transplantation for the treatment of retinal diseases enormous progress has been made. The potential for at least partial restoration of visual function has been shown in both animal experimentation and human clinical trials. Diseases that have shown reversal of vision loss from RPE transplantation include primary RPE dystrophies (RCS rat), photoreceptor dystrophies as well as complex retinal disease such as atrophic and neovascular AMD.
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