RETINAL PIGMENT EPITHELIUM TRANSPLANTATION

Progress in retinal pigment epithelium (RPE) transplantation has so far occurred in very small steps, observes Susanne Binder MD. Nevertheless, investigators remain optimistic that steady incremental advances may someday allow RPE transplantation to become a widely performed method for rehabilitating vision in patients with agerelated macular degeneration (AMD) and other retinal degenerative diseases. Speaking at the 2012 annual meeting of the Association for Research in Vision and Ophthalmology, Dr Binder discussed the current state of RPE transplantation and future directions by reviewing where the field has been and the challenges that investigators are attempting to overcome. She noted that RPE transplantation was first done in a human in 1991. To date, more than 600 cases have been performed. “Clinical investigation of RPE transplantation began after extensive experimental research established that transplanted RPE cells could rescue photoreceptors, and proof of principle was first provided in 2003 when Machemer and Steinberg showed that transfer of autologous adult human RPE from the extrafoveal region by 360 degree retinal translocation could restore foveal function,†said Dr Binder, professor and chair, department of ophthalmology, The Ludwig Boltzmann Institute for Retinology and Biomicroscopic Lasersurgery, Rudolf Foundation Clinic, Vienna, Austria. Research over the past two decades has focused on optimising the RPE cell source, the condition of the recipient site, and the transplantation technique.

Cell source issues

Dr Binder noted that her group became interested in using autologous RPE cell suspensions based on histopathologic evidence from animal studies showing the successful integration of cultured RPE cell suspensions in the subretinal space. However, while data from a consecutive series of patients showed subretinal membrane excision with simultaneous transplantation of an autologous RPE suspension was associated with a low complication rate, reduction in recurrent neovascularisation, improvements in subclinical tests, and improvement or stabilisation of vision, the use of aged cells and their placement in the “hostile†environment of an aged and defective Bruch’s membrane (BM) were limiting factors in achieving better outcomes. As an alternative, Dr Binder’s group and others investigated use of a full thickness RPE-BM-choroid patch.

However, their experience showed that visual acuity outcomes were no better than when transplanting the RPE cell suspension and proliferative vitreoretinopathy (PVR) developed at a rate of up to 45 per cent. Experiments have also been done using human foetal RPE cells. However, they are not considered a practical source for developing an RPE transplant paradigm considering that these cells show morphologic changes after just a few passages, have potential immunogenicity and are in limited supply. Embryonic stem cells can undergo largescale expansion and are pathogen-free. Human embryonic stem cell-derived RPE (hES-RPE) cells have been shown to be genetically similar to in situ RPE as well as to have better survival than aged adult RPE and iris pigment epithelial (IPE) cells when transplanted onto aged and diseased BM in laboratory experiments. Dr Binder noted that human pluripotent stem cells are thought to hold the greatest promise for the future. RPE cells derived from this source have been shown to be morphologically similar to native RPE cells, to express markers of developing and mature RPE cells, and are able to phagocytose photoreceptor outer segments.

Manipulating cells

Future success will also depend on identifying strategies for improving transplanted cell adhesion to BM and maintaining graft survival long-term. Experimentally, success has been achieved using bovine corneal endothelial cells as a matrix for foetal RPE or mitomycin-C treated fibroblasts as a feeder layer. “Reprogramming†of the RPE cells, either to rejuvenate aged cells in order to improve their likelihood of survival or to promote their expression of cytokines and trophic factors beneficial for the retina and choroid is also being investigated by various groups. Dr Binder noted she and her colleagues are involved in this type of research with studies aiming to rejuvenate RPE cells with epidermal growth factor and insulin growth factor and investigating a pigment epithelium derived cell-based gene therapy approach using autologous RPE or IPE cells. Research is also under way aimed at improving the recipient site through the development of a prosthetic BM. The purpose of this artificial basal lamina would be to serve as a scaffold to guide the repair and restoration of function to the damaged tissue while maintaining a clinically functional epithelial phenotype, Dr Binder explained. Various polymers have also been investigated for use as a prosthetic BM, including natural compounds such as collagen, gelatin and fibrinogen crosslinked in the presence of thrombin. These polymers are biocompatible and mimic the extracellular matrix of BM.

However, their absorption is unpredictable and use of these natural substances is also accompanied by concerns relating to possible disease transmission and allergenicity. Synthetic polymers offer the potential to overcome the latter limitations, and Dr Binder noted that her group has been working with electrospun polyamide nanofibres. In a recently published paper, they reported outcomes from an experiment in rabbit eyes where a foetal human RPE cell/polyester implant was embedded in a thermosensitive gelatin and introduced into the subretinal space using a specialised instrument. 'Cell-derived therapies are more difficult to perform than expected and progress happens in many small steps. This is related on one side to the difficulties we face during experiments but also to a lack of interest from the industry, because this kind of treatment will be less profitable than simple application of drugs. However, finally it is the way to go for curing so-far untreatable diseases,' Dr Binder concluded.