Ординатура / Офтальмология / Английские материалы / Retinal Degenerations biology, diagnostics, and therapeutics_Tombran-Tink, Barnstable_2007

93.Berglin L, Gouras P, Sheng YH, et al. Tolerance of human fetal retinal pigment epithelium xenografts in monkey retina. Graefes Arch Clin Exp Ophthalmol 1997;235:103–110.

94.Seaton AD, Sheedlo HJ, Turner JE. A primary role for RPE transplants in the inhibition and regression of neovascularization in the RCS rat. Invest Ophthalmol Vis Sci 1994;35:162–169.

95.Holmes TM, Lu B, Lund RD. Human RPE cell transplants retard the secondary vascular events of RCS rat retinal degeneration. Invest Ophthalmol Vis Sci 2003; Abstract no. 4972.

96.Klein RJ, Zeiss C, Chew EY, et al. Complement factor H polymorphism in age-related macular degeneration. Science 2005;308:385–389.

97.Haines JL, Hauser MA, Schmidt S, et al. Complement factor H variant increases the risk of age-related macular degeneration. Science 2005;308:419–421.

98.Edwards AO, Ritter R 3rd, Abel KJ, Manning A, Panhuysen C, Farrer LA. Complement factor H polymorphism and age-related macular degeneration. Science 2005;308:421–424.

99.Algvere P, Berglin L, Gouras P, et al. Transplantation of RPE in age-related macular degeneration: Observations in disciform lesions and dry RPE atrophy. Graefes Arch Clin Exp Ophthalmol 1997;235:149–158.

100.Bindewald A, Roth F, Van Meurs J, Holz FG. Transplantation of retinal pigment pithelium (RPE) following CNV removal in patients with AMD. Techniques, results, outlook. Ophthalmologe 2004;101:886–894.

101.Stanga PE, Kychenthal A, Fitzke FW, et al. Retinal pigment epithelium translocation and central visual function in age related macular degeneration: preliminary results. Int Ophthalmol 2001;23:297–307.

102.Tsukahara I, Ninomiya S, Castellarin A, Yagi F, Sugino IK, Zarbin MA. Early attachment of uncultured retinal pigment epithelium from aged donors onto Bruch’s membrane explants. Exp Eye Res 2002;74:255–266.

103.Algvere PV, Gouras P, Dafgard Kopp E. Long-term outcome of RPE allografts in non-immunosuppressed patients with AMD. Eur J Ophthalmol 1999;9:217–230.

104.Gullapalli VK, Sugino IK, Van Patten Y, Shah S, Zarbin MA. Retinal pigment epithelium resurfacing of aged submacular human Bruch’s membrane. Trans Am Ophthalmol Soc 2004;102:123–138.

105.Zarbin MA. Analysis of retinal pigment epithelium integrin expression and adhesion to aged submacular human Bruch’s membrane. Trans Am Ophthalmol Soc 2003;101: 499–520.

106.Tezel TH, Del Priore LV. Repopulation of different layers of host human Bruch’s membrane by retinal pigment epithelial cell grafts. Invest Ophthalmol Vis Sci 1999;40: 767–774.

107.Tezel TH, Kaplan HJ, Del Priore LV. Fate of human retinal pigment epithelial cells seeded onto layers of human Bruch’s membrane. Invest Ophthalmol Vis Sci 1999;40:467–476.

108.Binder S, Krebs I, Hilgers RD, et al. Outcome of transplantation of autologous retinal pigment epithelium in age-related macular degeneration: a prospective trial. Invest Ophthalmol Vis Sci 2004;45:4151–4160.

109.Machemer R, Steinhorst UH. Retinal separation, retinotomy, and macular relocation: II. A surgical approach for age-related macular degeneration? Graefes Arch Clin Exp Ophthalmol 1993;231:635–641.

110.Cahill MT, Mruthyunjaya P, Bowes Rickman C, Toth CA. Recurrence of retinal pigment epithelial changes after macular translocation with 360 degrees peripheral retinectomy for geographic atrophy. Arch Ophthalmol 2005;123:935–938.

111.Khurana RN, Fujii GY, Walsh AC, Humayun MS, de Juan E Jr, Sadda SR. Rapid recurrence of geographic atrophy after full macular translocation for nonexudative age-related macular degeneration. Ophthalmology 2005;112:1586–1591.

112.Ishida M, Lui GM, Yamani A, Sugino IK, Zarbin MA. Culture of human retinal pigment epithelial cells from peripheral scleral flap biopsies. Curr Eye Res 1998;17:392–402.

113.Engelmann K, Valtink M. RPE cell cultivation. Graefes Arch Clin Exp Ophthalmol 2004;242:65–67.

114.Greenwood J, Pryce G, Devine L, et al. SV40 large T immortalised cell lines of the rat blood-brain and blood-retinal barriers retain their phenotypic and immunological characteristics. J Neuroimmunol 1996;71:51–63.

115.Kanuga N, Winton HL, Beauchene L, et al. Characterization of genetically modified human retinal pigment epithelial cells developed for in vitro and transplantation studies. Invest Ophthalmol Vis Sci 2002;43:546–555.

116.Klimanskaya I, Hipp J, Rezai KA, West M, Atala A, Lanza R. Derivation and comparative assessment of retinal pigment epithelium from human embryonic stem cells using transcriptomics. Cloning Stem Cells 2004;6:217–245.

117.Dunn KC, Aotaki-Keen AE, Putkey FR, Hjelmeland LM. ARPE-19, a human retinal pigment epithelial cell line with differentiated properties. Exp Eye Res 1996;62:155–169.

118.Turowski P, Adamson P, Sathia J, et al. Basement membrane-dependent modification of phenotype and gene expression in human retinal pigment epithelial ARPE-19 cells. Invest Ophthalmol Vis Sci 2004;45:2786–2794.

119.Gamm D, Capowski B, Lu B, et al. Localization and rescue effect of human forebrain progenitor cells injected into the subretinal space of a rat photoreceptor degeneration model. Soc Neurosci 2005; Abstract no. 9777.

120.Wang S, Lu B, Wood P, Lund RD. Grafting of ARPE-19 and Schwann cells to the subretinal space in RCS rats. Invest Ophthalmol Vis Sci 2005;46:2552–2560.

121.Bush RA, Hawks KW, Sieving PA. Preservation of inner retinal responses in the aged Royal College of Surgeons rat. Evidence against glutamate excitotoxicity in photoreceptor degeneration. Invest Ophthalmol Vis Sci 1995;36:2054–2062.

122.Sauvé Y, Lu B, Lund RD. The relationship between full field electroretinogram and perimetry-like visual thresholds in RCS rats during photoreceptor degeneration and rescue by cell transplants. Vision Res 2003;20:100–112.

123.Girman SV, Wang S, Lund RD. Time course of deterioration of rod and cone function in RCS rat and the effects of subretinal cell grafting: a lightand dark-adaptation study. Vision Res 2005;45:343–354.

124.Sauvé Y, Girman SV, Wang S, Lawrence JM, Lund RD. Progressive visual sensitivity loss in the Royal College of Surgeons rat: perimetric study in the superior colliculus. Neuroscience 2001;103:51–63.

125.Li L, Turner JE. Optimal conditions for long-term photoreceptor cell rescue in RCS rats: the necessity for healthy RPE transplants. Exp Eye Res 1991;52:669–679.

126.Wang S, Girman S, Holmes T, Sauvé Y, Lu B, Lund RD. Morphological and functional rescue in RCS rats after RPE cell line transplantation at later stage of degeneration. Invest Ophthalmol Vis Sci 2005; Abstract no. 4145.

127.Leveillard T, Mohand-Said S, Lorentz O, et al. Identification and characterization of rod-derived cone viability factor. Nat Genet 2004;36:755–759.

128.Mata NL, Radu RA, Clemmons RC, Travis GH. Isomerization and oxidation of vitamin a in cone-dominant retinas: a novel pathway for visual-pigment regeneration in daylight. Neuron 2002;36:69–80.

129.Liu H, Ren JG, Cooper WL, Hawkins CE, Cowan MR, Tong PY. Identification of the antivasopermeability effect of pigment epithelium-derived factor and its active site. Proc Natl Acad Sci USA 2004;101:6605–6610.

130.Yamagishi S, Amano S, Inagaki Y, Okamoto T, Takeuchi M, Inoue H. Pigment epitheliumderived factor inhibits leptin-induced angiogenesis by suppressing vascular endothelial

growth factor gene expression through anti-oxidative properties. Microvasc Res 2003; 65:186–190.

131.Duh EJ, Yang HS, Suzuma I, et al. Pigment epithelium-derived factor suppresses ischemiainduced retinal neovascularization and VEGF-induced migration and growth. Invest Ophthalmol Vis Sci 2002;43:821–829.

132.Chader GJ. PEDF: Raising both hopes and questions in controlling angiogenesis. Proc Natl Acad Sci USA 2001;98:2122–2124.

133.Dawson DW, Volpert OV, Gillis P, et al. Pigment epithelium-derived factor: a potent inhibitor of angiogenesis. Science 1999;285:245–248.

134.Holmes TM, Lawrence JM, Butt RP, Lund RD. Development of retinal vascular complexes in the Royal College of Surgeons (RCS) rat and the effects of pharmaceutical intervention with pigment epothelial derived factor (PEDF) and echistatin. Invest Ophthalmol Vis Sci 2002; Abstract no. 34–86.

135.Dintelmann TS, Heimann K, Kayatz P, Schraermeyer U. Comparative study of ROS degradation by IPE and RPE cells in vitro. Graefes Arch Clin Exp Ophthalmol 1999;237:830–839.

136.Schraermeyer U, Kociok N, Heimann K. Rescue effects of IPE transplants in RCS rats: short-term results. Invest Ophthalmo Vis Sci 1999;40:1545–1556.

137.Schraermeyer U, Kayatz P, Thumann G, et al. Transplantation of iris pigment epithelium into the choroid slows down the degeneration of photoreceptors in the RCS rat. Graefes Arch Clin Exp Ophthalmol 2000;238:979–984.

138.Kano T, Abe T, Tomita H, Sakata T, Ishiguro S, Tamai M. Protective effect against ischemia and light damage of iris pigment epithelial cells transfected with the BDNF gene. Invest Ophthalmol Vis Sci 2002;43:3744–3753.

139.Hojo M, Abe T, Sugano E, et al. Photoreceptor protection by iris pigment epithelial transplantation transduced with AAV-mediated brain-derived neurotrophic factor gene. Invest Ophthalmol Vis Sci 2004;45:3721–3726.

140.Abe T, Yoshida M, Tomita H, et al. Auto iris pigment epithelial cell transplantation in patients with age-related macular degeneration: short-term results. Tohoku J Exp Med 2000;191:7–20.

141.Lappas A, Weinberger AW, Foerster AM, Kube T, Rezai KA, Kirchhof B. Iris pigment epithelial cell translocation in exudative age-related macular degeneration. A pilot study in patients. Graefes Arch Clin Exp Ophthalmol 2000;238:631–641.

142.Thumann G, Aisenbrey S, Schraermeyer U, et al. Transplantation of autologous iris pigment epithelium after removal of choroidal neovascular membranes. Arch Ophthalmol 2000;118:1350–1355.

143.Lappas A, Foerster AM, Weinberger AW, Coburger S, Schrage NF, Kirchhof B. Translocation of iris pigment epithelium in patients with exudative age-related macular degeneration: long-term results. Graefes Arch Clin Exp Ophthalmol 2004;242:638–647.

144.Semkova I, Kreppel F, Welsandt G, et al. Autologous transplantation of genetically modified iris pigment epithelial cells: a promising concept for the treatment of age-related macular degeneration and other disorders of the eye. Proc Natl Acad Sci USA 2002;99:13,090–13,095.

145.LaVail MM, Faktorovich EG, Hepler JM, et al. Basic fibroblast growth factor protects photoreceptors from light-induced degeneration in albino rats. Ann NY Acad Sci 1991;638:341–347.

146.Akimoto M, Miyatake S, Kogishi J, et al. Adenovirally expressed basic fibroblast growth factor rescues photoreceptor cells in RCS rats. Invest Ophthalmol Vis Sci 1999;40:273–279.

147.Wu WC, Lai CC, Chen SL, et al. Gene therapy for detached retina by adeno-associated virus vector expressing glial cell line-derived neurotrophic factor. Invest Ophthalmol Vis Sci 2002;43:3480–3488.

148.Hauswirth WW, Li Q, Raisler B, et al. Range of retinal diseases potentially treatable by AAV-vectored gene therapy. Novartis Found Symp 2004;255:179–194.

149.McGee Sanftner LH, Abel H, Hauswirth WW, Flannery JG. Glial cell line derived neurotrophic factor delays photoreceptor degeneration in a transgenic rat model of retinitis pigmentosa. Mol Ther 2001;4:622–629.

150.Machida S, Tanaka M, Ishii T, Ohtaka K, Takahashi T, Tazawa Y. Neuroprotective effect of hepatocyte growth factor against photoreceptor degeneration in rats. Invest Ophthalmol Vis Sci 2004;45:4174–4182.

151.Lau D, McGee LH, Zhou S, et al. Retinal degeneration is slowed in transgenic rats by AAV-mediated delivery of FGF-2. Invest Ophthalmol Vis Sci 2000;41:3622–3633.

152.Cayouette M, Smith SB, Becerra SP, Gravel C. Pigment epithelium-derived factor delays the death of photoreceptors in mouse models of inherited retinal degenerations. Neurobiol Dis 1999;6:523–532.

153.Lambiase A, Aloe L. Nerve growth factor delays retinal degeneration in C3H mice. Graefes Arch Clin Exp Ophthalmol 1996;234 Suppl 1:S96–S100.

154.Neuberger TJ, De Vries GH. Distribution of fibroblast growth factor in cultured dorsal root ganglion neurons and Schwann cells. II. Redistribution after neural injury. J Neurocytol 1993;22:449–460.

155.Sendtner M, Stockli KA, Thoenen H. Synthesis and localization of ciliary neurotrophic factor in the sciatic nerve of the adult rat after lesion and during regeneration. J Cell Biol 1992;118:139–148.

156.Meyer M, Matsuoka I, Wetmore C, Olson L, Thoenen H. Enhanced synthesis of brainderived neurotrophic factor in the lesioned peripheral nerve: different mechanisms are responsible for the regulation of BDNF and NGF mRNA. J Cell Biol 1992;119:45–54.

157.Ogilvie JM, Speck JD, Lett JM. Growth factors in combination, but not individually, rescue rd mouse photoreceptors in organ culture. Exp Neurol 2000;161:676–685.

158.Caffe AR, Soderpalm AK, Holmqvist I, Van Veen T. A combination of CNTF and BDNF rescues rd photoreceptors but changes rod differentiation in the presence of RPE in retinal explants. Invest Ophthalmo Vis Sci 2001;42:275–282.

159.Perry VH, Hayes L. Lesion-induced myelin formation in the retina. J Neurocytol 1985; 14:297–307.

160.Holmes T, Lu B, Sauvé Y, et al. Schwann cell therapy sustains long-term visual function in the Royal College of Surgeons rat. Invest Ophthalmol Vis Sci 2005; Abstract no. 1658.

161.Lawrence JM, Keegan DJ, Muir EM, et al. Transplantation of Schwann cell line clones secreting GDNF or BDNF into the retinas of dystrophic Royal College of Surgeons rats. Invest Ophthalmol Vis Sci 2004;45:267–274.

162.Li Y, Decherchi P, Raisman G. Transplantation of olfactory ensheathing cells into spinal cord lesions restores breathing and climbing. J Neurosci 2003;23:727–731.

163.Cao L, Liu L, Chen ZY, et al. Olfactory ensheathing cells genetically modified to secrete GDNF to promote spinal cord repair. Brain 2004;127:535–549.

164.Boruch AV, Conners JJ, Pipitone M, et al. Neurotrophic and migratory properties of an olfactory ensheathing cell line. Glia 2001;33:225–229.

165.Lipson AC, Widenfalk J, Lindqvist E, Ebendal T, Olson L. Neurotrophic properties of olfactory ensheathing glia. Exp Neurol 2003;180:167–171.

166.Lund R, Budko E, Lu B, et al. Assessment of olfactory ensheathing cells as a cell-based therapy to prevent photoreceptor degeneraion in the Royal College of Surgeons rat. Invest Ophthalmol Vis Sci 2005; Abstract no. 1653.

167.Mizumoto H, Mizumoto K, Whiteley SJ, Shatos M, Klassen H, Young MJ. Transplantation of human neural progenitor cells to the vitreous cavity of the Royal College of Surgeons rat. Cell Transplant 2001;10:223–233.

168.Young MJ, Ray J, Whiteley SJ, Klassen H, Gage FH. Neuronal differentiation and morphological integration of hippocampal progenitor cells transplanted to the retina of immature and mature dystrophic rats. Mol Cell Neurosci 2000;16:197–205.

169.Takahashi M, Palmer TD, Takahashi J, Gage FH. Widespread integration and survival of adult-derived neural progenitor cells in the developing optic retina. Mol Cell Neurosci 1998;12:340–348.

170.Arnhold S, Klein H, Semkova I, Addicks K, Schraermeyer U. Neurally selected embryonic stem cells induce tumor formation after long-term survival following engraftment into the subretinal space. Invest Ophthalmol Vis Sci 2004;45:4251–4255.

171.Banin E, Obolensky A, Idelson M, et al. Retinal incorporation and differentiation of neural precursors derived from human embryonic stem cells. Stem Cells 2006;24:246–257.

neovascularization (CNV) membranes into the subretinal space in eyes with age-related macular degeneration (AMD). Both of these conditions, retinal degeneration and AMD, are the most prevalent hereditary and age-related causes of severe loss of vision in the developed countries.

At present, there are no established and effective treatments for these diseases but partial success in rescuing photoreceptor cells have been attained by the transplantation of RPE cells (6,7) and iris pigment epithelial (IPE) cells in experimental animals (8). These experiments have been conducted on such animals as rd and rds mice, Royal College of Surgeon (RCS) and Fisher-344 rats, and the results suggested that transplantation of RPE cells may be an alternative treatment for human retinal diseases. Interestingly, the transplantation of pigmented cells or neural retina has already been performed on patients with retinitis pigmentosa (RP) or AMD.

In this chapter, I will review the basic and clinical studies that are related to the transplantation of IPE cells, and the results we have obtained with IPE transplantation as a developing therapy for RP and AMD.

EVIDENCE FOR RPE PROLIFERATION/MIGRATION OF RPE CELLS IN SUBRETINAL SPACE AND FUNCTIONAL RECOVERY

Clinical Observations of a Case

A 43-yr-old man was referred to Tohoku University Hospital because of a sudden development of a visual field defect in his right eye on November 16, 1991. His best corrected visual acuity was 0.5 ocular dexter (OD) and 1.5 ocular sinister (OS). The anterior segment of the right eye showed no signs of inflammation but a severe serous detachment was observed in the inferior half of the retina including macular area. His vision soon recovered to 1.5 OD, but a large RPE tear was found in the temporal posterior retina (Fig. 1A) under the detached retina that showed diffuse fluorescein leakage. The fovea centralis was spared, so his vision was still 1.5 OD. The detached RPE curled into a tight circular bundle as can be seen in Fig. 1A–G. Follow-up examination by ophthalmoscopy and fluorescein angiography showed a gradual increase of pigmentation and a decrease of fluorescein leakage, especially in the marginal zone with bared RPE. His vision was good, so we were able to follow his visual field changes precisely by Humphrey perimetry. Initially, the sensitivity corresponding to the bared area decreased, but there was a progressive recovery during the following 6 mo (Fig. 1B,E,H). We suggest that the functional recovery in this patient was the result of the proliferation and migration of RPE cells into the bared area just as in experimental animals (9).

RPE tears are not rare and can be found in patients with multiple posterior pigment epitheliopathy, and quite often in eyes with age-related RPE detachment. Repair of areas bared by laser photocoagulation have been observed in clinical cases (10). Because of the capricious recovery of the functional processes, an accurate visual prognosis is difficult in such cases.

A disturbance of Bruch’s membrane caused by the accumulation of debris, such as neutral lipids or phospholipids (11), has been suggested to be one of the factors affecting the repair of RPE cells. If an RPE tear happens in an elderly person, the visual

Fig. 1. Funds photographs, fluorescein angiograms, and Humphrey visual fields recorded at the follow-up periods indicated under each picture. Just after a large RPE tear developed, active fluorescein leakage with serous retinal detachment was observed in the bared area (A). About 3 wk later, perimetry showed a large visual defect corresponding to the RPE tear with better sensitivity at the RPE-remaining area (B). Follow-up examinations of fluorescein angiography (D,G) and perimetry (E,H) show the recovery of the barrier function of RPE-bared area and reduction of scotoma indicated by arrows and enlargement and better sensitivity in the area indicated by arrowheads.

prognosis is usually poor, but in younger persons, as shown here, reconstruction of the blood–retinal barrier and recovery of the retinal function of the torn area can occur.

Rearrangement and Function of Transplanted RPE Cells Under the Neural

Retina: Discrepancy Between Basic and Clinical Observations

RPE cells transplanted into the subretinal space can survive (monkey [12]), regenerate and proliferate (rabbit [9,13]; monkey [14]), rescue photoreceptor cells (RCS rats [15]), and delay the progression of age-related cell death (Fisher-344 rat [7]). Within 7 d after RPE ablation, the blood–retinal barrier function and tight junction complexes are restored by the infiltration of no-pigmented fibroblast-like cells in rabbits (8), and the density of regenerated RPE cells is increased by more than four times the preoperative level. These cells also secrete neurotrophic (NT) factors such as basic fibroblast

growth factor (bFGF) (13). The regenerated cells lack melanin and are undifferentiated, but after 9 mo, the repopulated RPE cells became pigmented. These observations indicate that RPE cells in the subretinal space can differentiate with a longer time period (14).

The surgical removal of subfoveal hemorrages and/or CNV membranes is performed as an alternative AMD treatment among vitreous surgeons in the developed countries. However, as the RPE cells constitute part or the margin of the CNV (16,17), surgical removal of a CNV must result in the loss of RPE cells. The mean number of cells lost has been calculated to be 1.52 × 104 cells (18,19; Fig. 2A). A functional recovery of the retina has been observed in some of these cases, but in many, the recovery of vision was to 0.1 or less (Fig. 2B). Moreover, the pigmented areas were not necessarily used as the fixation area as determined by microperimetry, and scotomas were present in some patients. These observations suggest that the proliferation and migration of residual RPE cells do not always lead to functional recovery under these clinical conditions, and the necessity of supplemental RPE cells or other types of cells may be necessary to obtained better vision.

COMPARISONS OF CHARACTERISTICS OF RPE AND IPE CELLS AND RESULTS OF SIMULTANEOUS SUBMACULAR SURGERY AND CULTURED AUTOLOGOUS IPE TRANSPLANTATION

IN EYES WITH AMD

Based on these basic and clinical observations, RPE cells were isolated from eye bank eyes or fetal human eyes and cultured for allograft transplantation in patients with AMD (20,21). Following transplantation, ophthalmoscopy showed a thickening in the transplanted area, and fluorescein angiography (FA) showed fluorescein leakage. With time, there was a gradual decrease of vision suggesting a host-graft rejection, and these patients required careful monitoring for tissue rejection (22,23).

On the other hand, the transplantation of autologous RPE cells into eyes with exudative AMD was reported to improve the visual acuity (24,25). These results indicate that the subretinal space was not a completely immunologically privileged site (26), and systemic immunity can exert a significant influence on nonautologous transplanted cells into the subretinal space when there is a breakdown of the blood–retinal barrier (27). Thus, allograft transplantation can elicit host-graft rejection in humans even if the intraocular space is considered to be immunologically privileged.

To avoid or minimize the host-graft rejection in patients, autologous cells should be used, and IPE cells may be the best alternative to RPE cells, because IPE cells have the same embryonic origin and sufficient numbers can be easily obtained by peripheral iridectomy.

Comparisons of RPE and IPE Cells

Methods of Culture and Proliferation Rates

The isolation and culturing of RPE and IPE cells have been reported in detail (28,29). In brief, after removing the anterior segment and vitreous from eyes, the eyecups are incubated in a calciumand magnesium-free Hank’s balanced salt solution (HBSS) supplemented with trypsin (0.05%)/ethylenediaminetetraaminicacid (EDTA; 0.53 mM) for 40 min at 37°C in a 5% CO2 incubator. Human IPE cells were separated from the