Cell-based Therapies for AMD - a Cure on the Horizon?
While most of the ophthalmologic world concentrates on anti-VEGF therapies for AMD, steady progress has been made in the field of retinal pigment epithelium (RPE) transplantation.
Among many other functions, the RPE secretes and responds to numerous growth factors and other cytokines; two of them are VEGF (here the RPE balances production versus inhibition) and pigment epithelium derived factor (PEDF) which acts as a key coordinator of retinal neuronal and vascular functions and is a potent inhibitor of angiogenesis (1,2). In contrast to targeted inhibition of a single growth factor, cell-based therapies attempt to restore a more normal retinal condition and, thus, could provide stable long term results and, hopefully, reversal of visual loss. In addition, patients with dry AMD or other retinal degenerations, for which no other cure is currently available, might be candidates for RPE transplantation.
More than 20 years ago, Peter Gouras published his work on RPE transplantation (3). Animal experiments have shown with convincing evidence the ability of transplanted RPE to rescue photoreceptors (PR) and preserve vision in retinal degeneration (4). However, in human studies with patients suffering from advanced stages of AMD, visual gain was rather modest.
There are several potential reasons for RPE transplant failure in humans. One of these is immune rejection (5). Elderly patients may not be able to tolerate long term combined immunosuppressive therapies if homologous transplants are used (6). In addition, cell aging and numbers for transplantation, the condition of the recipient bed, and surgical trauma are important factors (7).
Since the late 1990s, autologous RPE cells have been used for RPE transplantation and surgical techniques have become more refined (8). Full thickness autologous RPE-Bruch’s membrane-choroid transplants, taken primarily from areas close to the excised membrane (9) or from the mid periphery, are currently used by several groups for both exudative and dry AMD (10-12). As a less traumatic technique, RPE suspensions, freshly harvested from the subretinal area, have been also transplanted in patients with exudative AMD (13,14). While the disadvantage of the patch is possible sequestration or intralaminar gliosis over time and rather high complication rates, it carries the advantage of translocating a polarized layer of RPE on an intact basal lamina where vascularization of the graft can be achieved; this has been demonstrated both in experiments and also in clinical cases (14). When transplanting a suspension of viable cells, cell amounts and the status of the recipient bed are important. Deep and large defects of Bruch`s membrane do not repopularize well when aged RPE cells are used (15). Not surprisingly, eyes with small lesions in younger patients (under 60) showed better visual outcome than older patients, and smaller lesions demonstrated a better overgrowth of RPE than very large lesions with this technique, which carries a low risk of retinal complications and surgical failure (16) .
As anti-VEGF intravitreal injections are now the first line treatment in exudative AMD, candidates for RPE transplantation in the last two years have been limited either to very large lesions (“non responders” to intravitreal pharmacotherapy, meaning further lesion growth combined with progression of photoreceptor damage) and complications such as large hemorrhages and/or RPE rips. These cases are clearly not ideal settings in which to evaluate the potential of cell-based therapies.
To date, results of about 350 autologous RPE transplant cases have been reported. Stabilization of vision was achieved in most of the transplant cases, and low recurrence rates have been observed--4.4%, 13.3 % and 15 % after 12, 24 and 36 months, respectively (17). In most studies, a mean gain of one line of visual acuity was observed and, in those series without complications, a >3 line gain is reported in 8.8%-37% of cases. In contrast, complications are associated with a loss of vision (9-15). As most of these studies were consecutive case series, results cannot be compared directly to results of multicenter prospective trials. However, reported results of RPE transplantation are not as favourable as the results reported in the ranibizumab ( Lucentis*) trials, in which 25-40 % of patients achieved a >3 line visual acuity gain and 95% achieved visual stabilization (18,19). Whether patients who undergo RPE transplants maintain vision better on a long term basis remains to be seen but this could only be answered by a comparative randomized prospective trial.
Currently, patients who undergo RPE transplantation are generally those not suitable for other trials, usually with a visual acuity too low to meet inclusion criteria of clinical trials. As the status of the photoreceptors is an important factor in transplantation, selection of cases in which potential to regain photoreceptor function exists is necessary. Such cases include fresh RPE rips and early dry AMD.
To date, a good integration in the recipient bed, vascularization of the patch and significant subclinical functional gain with mERG and microperimetry, stabilization of vision and a low recurrence rate have been achieved with RPE transplantation, but one would wish more—namely, visual improvement in a considerable proportion of patients and long lasting results without monthly treatments.
Currently, research in this field is aiming in two directions: one is the rejuvenation of aged RPE for better survival and/or possible ex-vivo RPE-gene transfer before transplantation (20,12), and the other is the development of artificial basal laminas like Bruch`s membrane prosthesis which can be well tolerated in the subretinal space and biodegrade or integrate over time (21,23). In addition, new cell sources might become available like embryonic stem cells and retinal progenitor cells as well as retinal bone marrow derived stem cells (24). A lot has been learned about surgical techniques and more refined instrumentation is being developed. The addition of therapies improving cell integration and preventing glial reactions during and after transplantation needs to be explored as well.
Taken together, considerable progress has been made in the field of retinal transplantation. Its potential application to all forms of retinal degeneration makes it a worthwhile therapeutic endeavour. In AMD, some restoration of vision has been shown in unfavourable cases. Clearly, the future of cell-based therapies will be connected with advances in other fields of retinal research. The horizon is still distant but we are much closer now.
Campochiaro, P.A., 1993. Cytokine production by retinal pigmented epithelial cells. Int Rev Cytol. 146, 75-82.
Dawson, D.W., Volpert, O.V., Gillis, P., Crawford, S.E., Xu, H., Benedict, W. and Bouck, N.P., 1999. Pigment epithelium-derived factor: a potent inhibitor of angiogenesis. Science. 285, 245-8
Gouras, P., Flood, M.T. Eggers HM and Kjedbye H., 1983. Transplantation of human retinal cells to Bruch`s membrane in monkey eye. Invest Opthalmol vis Sci. 24(S) 142
Gouras P,.Lopez R, Kjeldbye H, Sullivan B, Brittis M. 1989. Transplantation of retinal pigment epithelium prevents photoreceptor degeneration in RCS rat. Prog. Clin. Biol. Res. 314,659-671
Grisanti, S., Ishioka, M., Kosiewicz, M. and Jiang, L.Q. 1997. Immunity and immune privilege elicited by cultured retinal pigment epithelial cell transplants. Invest Ophthalmol Vis Sci. 38, 1619-26.
Tezel T., Del Priore LV Berger A, Kaplan H. 2007. Adult Retinal Pigment Epithelial Transplantation in Exudative Age-related Macular degeneration. 2007 Am J Ophthalmol ,143: 584-95
Boulton M.2004. Aging of the retinal pigment epithelium : implications for transplantation . Graefes Arch Clin Exp Ophthalmol 242; 76-84
Algvere PV, Berglin L, Gouras p, Sheng Y and Kopp ED. 1997 Transplantation of RPE in age-related macular degeneration : observations in diciform lesions and dry RPE atrophy.. Graefes Arch Clin Exp Ophthalmol 9, 217-30
Stanga, P.E., Kychenthal, A., Fitzke, F.W., Halfyard, A.S., Chan, R., Bird, A.C. and Aylward, G.W., 2002. Retinal pigment epithelium translocation after choroidal neovascular membrane removal in age-related macular degeneration. Ophthalmology. 109, 1492-8
Brown, D. M. et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 355, 1432-44 (2006).
van Meurs JC, van den Biesen PR. 2003. Autologous retinal pigment epithelium and choroid translocation in patients with exudative age- related macular degeneration : short- term follow-up. Am J Ophthalmol . 136, 688-95
Mc Laren RE, Uppal GS, Ballagan Ks, Tufail AD, Munro PM, Ali RR, Aylward GW and Da Cruz ,.2007. Autologous transplantation of the retinal pigment epithelium in the treatment of neovascular age-related macular degeneration. Ophthalmology 114, 561-70
Binder, S., Stolba, U., Krebs, I., Kellner, L., Jahn, C., Feichtinger, H., Povelka, M., Frohner, U., Kruger, A., Hilgers, R.D. and Krugluger, W., 2002. Transplantation of autologous retinal pigment epithelium in eyes with foveal neovascularization resulting from age-related macular degeneration: a pilot study. Am J Ophthalmol. 133, 215-225.
Binder, S., Krebs, I., Hilgers, R.D., Abri, A., Stolba, U., Assadoulina, A., Kellner, L., Stanzel, B.V., Jahn, C. and Feichtinger, H., 2004. Outcome of transplantation of autologous retinal pigment epithelium in age-related macular degeneration: a prospective trial. Invest Ophthalmol Vis Sci. 45, 4151- 60.
Maaijewe KJ, van Meurs JC, Kirchof B, Mooij NM, Makiewitz J, Kobuch K and Joussen AM. 2006. Histological evidence for revscularisation of an autologous RPE-choroid graft in the pig. Brit J Ophthalmol 91, 546-50
Zarbin, M.A., 2003. Analysis of retinal pigment epithelium integrin expression and adhesion to aged submacular human Bruch's membrane. Trans Am Ophthalmol Soc. 101, 499-520.
Binder S, Stanzel BV, Krebs I and Glittenberg C, 2007. Transplantation of the RPE in AMD. Progress in Retina and Eye Research 26, 516-54
Brown DM, Kaiser PK, michels M, Soubrane G, Heier J, Kim RY, Sy JP and Schneider S, 2006.Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 355, 1432-1444 Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY and Kim RY.2006.Ranibizumab for neovsacular age related macular degeneration . N Engl J Med 355, 1419-31
Steindl K, Krugluger W, Boulton M, Binder S. 2008. Rejuvenation of RPE. A model using the ARPE 19 cell line. Submitted
Thumann G 1997. Descemet`s membrane as membranous support in RPE/IPE transplantation. Curr Eye Res, 16, 1236-38
Stanzel BV, Scheffer T, JM . Parel, Binder S .2005. Amniotic membrane maintains the phenotype of rabbit retinal pigment epithelial cells in culture. Exp Eye Res 80, 103.12
Stanzel BV, Englander M, Huie P, Blumenkranz M, Binder s, Marmor M , 2007, Towards prosthetic replacementof Bruch`s membrane : Comparison of polyester and electrospun nanofiber membranes. DOG Poster Award, submitted Exp Eye Res. 2008
Vugler A, Lawrence J, Walsh J, Carr A, Gias C, Semo M, Amado A, Da Cruz L, Andrews P, Coffey P. 2007. Embryonic stem cells and retinal repair. Mechanisms of Development 124, 807-829
About our author(s):
Susanne Binder MD
Professor and Chair
Department of Ophthalmology
The Ludwig Boltzmann Institute for Retinology and Biomicroscopic Lasersurgery
Rudolf Foundation Clinic