The progress of cell-replacement therapy for age-related macular degeneration_Chinese Journal of Ocular Fundus Diseases

Authors：

ShenHan ,  LiuQinghuai , YuanSongtao

Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China;

Corresponding author：

Keywords：

Macular degeneration/therapy; Retinal pigment epithelium; Cell transplantation; Review

DOI：

10.3760/cma.j.issn.1005-1015.2016.01.026

Video：

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Based on the pathogenic mechanisms of age-related macular degeneration (AMD), tremendous preclinical and clinical trials have demonstrated that cell transplantation which aim to replace impaired retinal pigment epithelium (RPE) with healthy RPE cells is a promising approach to treat AMD. So far, choices of cell sources mainly are autologous RPE, iris pigment epithelium, fetal RPE, human embryonic stem cell-derived RPE and human induced pluripotent stem cell-derived RPE, and some of them are undergoing clinical researches. Grafting manners in cell-based therapies are various including RPE sheet or RPE-choroid complex transplantation, RPE cell suspension injection, and RPE sheet transplantation with scaffolds. This review is limited to cell-based therapies for RPE that damaged first in the progress of AMD and focus on recent advances in cell sources, transplantation methods, preclinical and clinical trials, and the obstacles that must be overcome.

Citation： ShenHan, LiuQinghuai, YuanSongtao. The progress of cell-replacement therapy for age-related macular degeneration. Chinese Journal of Ocular Fundus Diseases, 2016, 32(1): 92-96. doi: 10.3760/cma.j.issn.1005-1015.2016.01.026 Copy

1.	Hubschman JP, Reddy S, Schwartz SD. Age-related macular degeneration: current treatments [J].Clin Ophthalmol, 2009,3:155-166.
2.	Holz FG, Pauleikhoff D, Spaide RF,et al. Age-related macular degeneration[M]. 2nd ed. Berlin: Springer, 2013:3-7.
3.	Peyman GA, Blinder KJ, Paris CL,et al.A technique for retinal pigment epithelium transplantation for age-related macular degeneration secondary to extensive subfoveal scarring[J].Ophthalmic Surg,1991,22(2):102-108.
4.	Ma Z, Han L, Wang C, et al. Autologous transplantation of retinal pigment epithelium-Bruch′s membrane complex for hemorrhagic age-related macular degeneration[J].Invest Ophthalmol Vis Sci,2009,50(6):2975-2981. DOI: 10.1167/iovs.08-2573.
5.	Han L, Ma Z, Wang C,et al. Autologous transplantation of simple retinal pigment epithelium sheet for massive submacular hemorrhage associated with pigment epithelium detachment[J].Invest Ophthalmol Vis Sci,2013,54(7):4956-4963. DOI: 10.1167/iovs.13-11957.
6.	Abe T, Yoshida M, Tomita H, et al.Functional analysis after auto iris pigment epithelial cell transplantation in patients with age-related macular degeneration[J]. Tohoku J Exp Med,1999,189(4):295-305.
7.	Abe T, Yoshida M, Tomita H, et al.Auto iris pigment epithelial cell transplantation in patients with age-related macular degeneration: short-term results[J]. Tohoku J Exp Med, 2000,191(1):7-20.
8.	Abe T, Yoshida M, Yoshioka Y, et al.Iris pigment epithelial cell transplantation for degenerative retinal diseases[J]. Prog Retin Eye Res,2007,26(3):302-321.
9.	Lappas A, Weinberger AW, Foerster AM, et al.Iris pigment epithelial cell translocation in exudative age-related macular degeneration. A pilot study in patients[J]. Graefe′s Arch Clin Exp Ophthalmol, 2000,238(8):631-641.
10.	Lappas A, Foerster AM, Weinberger AW, et al.Translocation of iris pigment epithelium in patients with exudative age-related macular degeneration: long-term results[J]. Graefe′s Arch Clin Exp Ophthalmol,2004,242(8):638-647.
11.	Thumann G. Development and cellular functions of the iris pigment epithelium[J]. Surv Ophthalmol, 2001,45(4):345-354.
12.	Rezai KA, Kohen L, Wiedemann P, et al. Iris pigment epithelium transplantation[J]. Graefe′s Arch Clin Exp Ophthalmol, 1997,235(9):558-562.
13.	Cai H, Shin MC, Tezel TH, et al. Use of iris pigment epithelium to replace retinal pigment epithelium in age-related macular degeneration: a gene expression analysis[J].Arch Ophthalmol, 2006,124(9):1276-1285.
14.	Kamao H, Mandai M, Okamoto S, et al.Characterization of human induced pluripotent stem cell-derived retinal pigment epithelium cell sheets aiming for clinical application[J]. Stem Cell Reports,2014,2(2):205-218. DOI: 10.1016/j.stemcr.2013.12.007.
15.	Carr AJ, Vugler AA, Hikita ST, et al. Protective effects of human iPS-derived retinal pigment epithelium cell transplantation in the retinal dystrophic rat[J/OL]. PLoS One,2009, 4(12): 8152[2009-12-03]. http://www.ncbi. nlm.nih.gov/pmc/ articles /PMC2780911/.DOI: 10.1371/journal.pone.0008152.
16.	Sohn EH, Jiao C, Kaalberg E, et al.Allogenic iPSC-derived RPE cell transplants induce immune response in pigs: a pilot study[J]. Sci Rep,2015,5:11791. DOI: 10.1038/srep11791.
17.	Zimmermann A, Preynat-Seauve O, Tiercy JM, et al.Haplotype-based banking of human pluripotent stem cells for transplantation:potential and limitations[J]. Stem Cells Dev, 2012,21(13):2364-2373. DOI: 10.1089/scd.2012.0088.
18.	Laurent LC, Ulitsky I, Slavin I, et al. Dynamic changes in the copy number of pluripotency and cell proliferation genes in human ESCs and iPSCs during reprogramming and time in culture[J]. Cell Stem Cell,2011,8(1):106-118. DOI: 10.1016/j.stem.2010.12.003.
19.	Gore A, Li Z, Fung HL, et al. Somatic coding mutations in human induced pluripotent stem cells[J]. Nature,2011,471(7336):63-67. DOI: 10.1038/nature09805.
20.	Reardon S, Cyranoski D. Japan stem-cell trial stirs envy[J]. Nature, 2014, 513(7518):287-288. DOI: 10.1038/513287a.
21.	Schwartz SD, Hubschman JP, Heilwell G,et al.Embryonic stem cell trials for macular degeneration: a preliminary report[J].Lancet, 2012,379(9817):713-720. DOI: 10.1016/S0140-6736(12)60028-2.
22.	Falkner-Radler CI, Krebs I, Glittenberg C, et al. Human retinal pigment epithelium (RPE) transplantation: outcome after autologous RPE-choroid sheet and RPE cell-suspension in a randomised clinical study[J].Br J Ophthalmol, 2011,95(3):370-375. DOI: 10.1136/bjo.2009.176305.
23.	Sowden JC. ESC-derived retinal pigmented epithelial cell transplants in patients: so far, so good[J]. Cell Stem Cell,2014,15(5):537-538. DOI: 10.1016/j.stem.2014.10.008.
24.	Song WK, Park KM, Kim HJ,et al. Treatment of macular degeneration using embryonic stem cell-derived retinal pigment epithelium: preliminary results in asian patients[J]. Stem Cell Reports,2015,4(5):860-872. DOI: 10.1016/j.stemcr.2015.04.005.
25.	Carr AJ, Smart MJ, Ramsden CM,et al.Development of human embryonic stem cell therapies for age-related macular degeneration[J].Trends Neurosci, 2013,36(7):385-395. DOI: 10.1016/j.tins.2013.03.006.
26.	Algvere PV, Berglin L, Gouras P, et al.Transplantation of fetal retinal pigment epithelium in age-related macular degeneration with subfoveal neovascularization[J]. Graefe′s Arch Clin Exp Ophthalmol, 1994,232(12):707-716.
27.	Algvere PV, Berglin L, Gouras P, et al .Transplantation of RPE in age-related macular degeneration: observations in disciform lesions and dry RPE atrophy[J]. Graefe′s Arch Clin Exp Ophthalmol, 1997,235(3):149-158.
28.	Weisz JM, Humayun MS, De Juan E Jr,et al.Allogenic fetal retinal pigment epithelial cell transplant in a patient with geographic atrophy[J].Retina,1999,19(6):540-545.
29.	Radtke ND, Aramant RB, Seiler MJ, et al .Vision change after sheet transplant of fetal retina with retinal pigment epithelium to a patient with retinitis pigmentosa[J]. Arch Ophthalmol, 2004,122(8):1159-1165.
30.	Radtke ND, Aramant RB, Petry HM, et al .Vision improvement in retinal degeneration patients by implantation of retina together with retinal pigment epithelium[J].Am J Ophthalmol,2008,146(2):172-182. DOI: 10.1016/j.ajo.2008.04.009.
31.	Rezai KA, Semnani RT, Patel SC, et al.The immunogenic potential of human fetal retinal pigment epithelium and its relation to transplantation[J].Invest Ophthalmol Vis Sci, 1997,38(12):2662-2671.
32.	袁松涛, 薛志刚, 林卿, 等.胎儿视网膜色素上皮细胞的原代培养和体外增殖能力的测定[J/CD].中华细胞与干细胞杂志:电子版,2014,4(1):16-20. DOI: 10.3877/cma.j.issn.2095-1221.2014.01.003.
33.	Cereda MG, Parolini B, Bellesini E,et al.Surgery for CNV and autologous choroidal RPE patch transplantation: exposing the submacular space[J].Graefe′s Arch Clin Exp Ophthalmol, 2010,248(1):37-47. DOI: 10.1007/s00417-009-1201-8.
34.	Chen FK, Uppal GS, MacLaren RE,et al.Long-term visual and microperimetry outcomes following autologous retinal pigment epithelium choroid graft for neovascular age-related macular degeneration[J].Clin Experiment Ophthalmol, 2009,37(3):275-285. DOI: 10.1111/j.1442-9071.2009.01915.x.
35.	Schwartz SD, Regillo CD, Lam BL, et al. Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt′s macular dystrophy: follow-up of two open-label phase 1/2 studies[J]. Lancet,2015,385 (9967):509-516. DOI: 10.1016/S0140-6736(14)61376-3.
36.	Binder S. Scaffolds for retinal pigment epithelium (RPE) replacement therapy[J].Br J Ophthalmol,2011,95(4):441-442. DOI:10.1136/bjo.2009.171926.
37.	Kundu J, Michaelson A, Baranov P, et al. Approaches to cell delivery: substrates and scaffolds for cell therapy[J].Dev Ophthalmol,2014,53:143-154. DOI: 10.1159/000357369.
38.	Song MJ, Bharti K. Looking into the future: using induced pluripotent stem cells to build two and three dimensional ocular tissue for cell therapy and disease modeling[J/OL]. Brain Res,2016,1598:E1[2015-12-17]. http://www.sciencedirect.com/science/article/pii/s0006899315009506.DOI: 10.1016/j.brainres.2015.12.011.[publisheaheadofprint].
39.	Krishna Y, Sheridan C, Kent D, et al.Expanded polytetra-fluoroethylene as a substrate for retinal pigment epithelial cell growth and transplantation in age-related macular degeneration[J].Br J Ophthalmol, 2011,95(4):569-573.DOI: 10.1136/bjo.2009.169953.
40.	Assawachananont J, Mandai M, Okamoto S,et al. Transplantation of embryonic and induced pluripotent stem cell-derived 3D retinal sheets into retinal degenerative mice[J]. Stem Cell Reports, 2014,2(5): 662-674.DOI:10.1016/j.stemcr.2014.03.011.
41.	John S, Natarajan S, Parikumar P,et al. Choice of cell source in cell-based therapies for retinal damage due to age-related macular degeneration: a review[J/OL]. J Ophthalmol, 2013,2013:465169[2013-03-05].http://dx.doi.org/10.1155/2013/465169. DOI: 10.1155/2013/465169.
42.	Fernández-Robredo P, Sancho A, Johnen S, et al. Current treatment limitations in age-related macular degeneration and future approaches based on cell therapy and tissue engineering[J/OL]. J Ophthalmol, 2014, 2014:510285 [2014-01-14]. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3941782/.DOI:10.1155/2014/510285.

1. Hubschman JP, Reddy S, Schwartz SD. Age-related macular degeneration: current treatments [J].Clin Ophthalmol, 2009,3:155-166.
2. Holz FG, Pauleikhoff D, Spaide RF,et al. Age-related macular degeneration[M]. 2nd ed. Berlin: Springer, 2013:3-7.
3. Peyman GA, Blinder KJ, Paris CL,et al.A technique for retinal pigment epithelium transplantation for age-related macular degeneration secondary to extensive subfoveal scarring[J].Ophthalmic Surg,1991,22(2):102-108.
4. Ma Z, Han L, Wang C, et al. Autologous transplantation of retinal pigment epithelium-Bruch′s membrane complex for hemorrhagic age-related macular degeneration[J].Invest Ophthalmol Vis Sci,2009,50(6):2975-2981. DOI: 10.1167/iovs.08-2573.
5. Han L, Ma Z, Wang C,et al. Autologous transplantation of simple retinal pigment epithelium sheet for massive submacular hemorrhage associated with pigment epithelium detachment[J].Invest Ophthalmol Vis Sci,2013,54(7):4956-4963. DOI: 10.1167/iovs.13-11957.
6. Abe T, Yoshida M, Tomita H, et al.Functional analysis after auto iris pigment epithelial cell transplantation in patients with age-related macular degeneration[J]. Tohoku J Exp Med,1999,189(4):295-305.
7. Abe T, Yoshida M, Tomita H, et al.Auto iris pigment epithelial cell transplantation in patients with age-related macular degeneration: short-term results[J]. Tohoku J Exp Med, 2000,191(1):7-20.
8. Abe T, Yoshida M, Yoshioka Y, et al.Iris pigment epithelial cell transplantation for degenerative retinal diseases[J]. Prog Retin Eye Res,2007,26(3):302-321.
9. Lappas A, Weinberger AW, Foerster AM, et al.Iris pigment epithelial cell translocation in exudative age-related macular degeneration. A pilot study in patients[J]. Graefe′s Arch Clin Exp Ophthalmol, 2000,238(8):631-641.
10. Lappas A, Foerster AM, Weinberger AW, et al.Translocation of iris pigment epithelium in patients with exudative age-related macular degeneration: long-term results[J]. Graefe′s Arch Clin Exp Ophthalmol,2004,242(8):638-647.
11. Thumann G. Development and cellular functions of the iris pigment epithelium[J]. Surv Ophthalmol, 2001,45(4):345-354.
12. Rezai KA, Kohen L, Wiedemann P, et al. Iris pigment epithelium transplantation[J]. Graefe′s Arch Clin Exp Ophthalmol, 1997,235(9):558-562.
13. Cai H, Shin MC, Tezel TH, et al. Use of iris pigment epithelium to replace retinal pigment epithelium in age-related macular degeneration: a gene expression analysis[J].Arch Ophthalmol, 2006,124(9):1276-1285.
14. Kamao H, Mandai M, Okamoto S, et al.Characterization of human induced pluripotent stem cell-derived retinal pigment epithelium cell sheets aiming for clinical application[J]. Stem Cell Reports,2014,2(2):205-218. DOI: 10.1016/j.stemcr.2013.12.007.
15. Carr AJ, Vugler AA, Hikita ST, et al. Protective effects of human iPS-derived retinal pigment epithelium cell transplantation in the retinal dystrophic rat[J/OL]. PLoS One,2009, 4(12): 8152[2009-12-03]. http://www.ncbi. nlm.nih.gov/pmc/ articles /PMC2780911/.DOI: 10.1371/journal.pone.0008152.
16. Sohn EH, Jiao C, Kaalberg E, et al.Allogenic iPSC-derived RPE cell transplants induce immune response in pigs: a pilot study[J]. Sci Rep,2015,5:11791. DOI: 10.1038/srep11791.
17. Zimmermann A, Preynat-Seauve O, Tiercy JM, et al.Haplotype-based banking of human pluripotent stem cells for transplantation:potential and limitations[J]. Stem Cells Dev, 2012,21(13):2364-2373. DOI: 10.1089/scd.2012.0088.
18. Laurent LC, Ulitsky I, Slavin I, et al. Dynamic changes in the copy number of pluripotency and cell proliferation genes in human ESCs and iPSCs during reprogramming and time in culture[J]. Cell Stem Cell,2011,8(1):106-118. DOI: 10.1016/j.stem.2010.12.003.
19. Gore A, Li Z, Fung HL, et al. Somatic coding mutations in human induced pluripotent stem cells[J]. Nature,2011,471(7336):63-67. DOI: 10.1038/nature09805.
20. Reardon S, Cyranoski D. Japan stem-cell trial stirs envy[J]. Nature, 2014, 513(7518):287-288. DOI: 10.1038/513287a.
21. Schwartz SD, Hubschman JP, Heilwell G,et al.Embryonic stem cell trials for macular degeneration: a preliminary report[J].Lancet, 2012,379(9817):713-720. DOI: 10.1016/S0140-6736(12)60028-2.
22. Falkner-Radler CI, Krebs I, Glittenberg C, et al. Human retinal pigment epithelium (RPE) transplantation: outcome after autologous RPE-choroid sheet and RPE cell-suspension in a randomised clinical study[J].Br J Ophthalmol, 2011,95(3):370-375. DOI: 10.1136/bjo.2009.176305.
23. Sowden JC. ESC-derived retinal pigmented epithelial cell transplants in patients: so far, so good[J]. Cell Stem Cell,2014,15(5):537-538. DOI: 10.1016/j.stem.2014.10.008.
24. Song WK, Park KM, Kim HJ,et al. Treatment of macular degeneration using embryonic stem cell-derived retinal pigment epithelium: preliminary results in asian patients[J]. Stem Cell Reports,2015,4(5):860-872. DOI: 10.1016/j.stemcr.2015.04.005.
25. Carr AJ, Smart MJ, Ramsden CM,et al.Development of human embryonic stem cell therapies for age-related macular degeneration[J].Trends Neurosci, 2013,36(7):385-395. DOI: 10.1016/j.tins.2013.03.006.
26. Algvere PV, Berglin L, Gouras P, et al.Transplantation of fetal retinal pigment epithelium in age-related macular degeneration with subfoveal neovascularization[J]. Graefe′s Arch Clin Exp Ophthalmol, 1994,232(12):707-716.
27. Algvere PV, Berglin L, Gouras P, et al .Transplantation of RPE in age-related macular degeneration: observations in disciform lesions and dry RPE atrophy[J]. Graefe′s Arch Clin Exp Ophthalmol, 1997,235(3):149-158.
28. Weisz JM, Humayun MS, De Juan E Jr,et al.Allogenic fetal retinal pigment epithelial cell transplant in a patient with geographic atrophy[J].Retina,1999,19(6):540-545.
29. Radtke ND, Aramant RB, Seiler MJ, et al .Vision change after sheet transplant of fetal retina with retinal pigment epithelium to a patient with retinitis pigmentosa[J]. Arch Ophthalmol, 2004,122(8):1159-1165.
30. Radtke ND, Aramant RB, Petry HM, et al .Vision improvement in retinal degeneration patients by implantation of retina together with retinal pigment epithelium[J].Am J Ophthalmol,2008,146(2):172-182. DOI: 10.1016/j.ajo.2008.04.009.
31. Rezai KA, Semnani RT, Patel SC, et al.The immunogenic potential of human fetal retinal pigment epithelium and its relation to transplantation[J].Invest Ophthalmol Vis Sci, 1997,38(12):2662-2671.
32. 袁松涛, 薛志刚, 林卿, 等.胎儿视网膜色素上皮细胞的原代培养和体外增殖能力的测定[J/CD].中华细胞与干细胞杂志:电子版,2014,4(1):16-20. DOI: 10.3877/cma.j.issn.2095-1221.2014.01.003.
33. Cereda MG, Parolini B, Bellesini E,et al.Surgery for CNV and autologous choroidal RPE patch transplantation: exposing the submacular space[J].Graefe′s Arch Clin Exp Ophthalmol, 2010,248(1):37-47. DOI: 10.1007/s00417-009-1201-8.
34. Chen FK, Uppal GS, MacLaren RE,et al.Long-term visual and microperimetry outcomes following autologous retinal pigment epithelium choroid graft for neovascular age-related macular degeneration[J].Clin Experiment Ophthalmol, 2009,37(3):275-285. DOI: 10.1111/j.1442-9071.2009.01915.x.
35. Schwartz SD, Regillo CD, Lam BL, et al. Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt′s macular dystrophy: follow-up of two open-label phase 1/2 studies[J]. Lancet,2015,385 (9967):509-516. DOI: 10.1016/S0140-6736(14)61376-3.
36. Binder S. Scaffolds for retinal pigment epithelium (RPE) replacement therapy[J].Br J Ophthalmol,2011,95(4):441-442. DOI:10.1136/bjo.2009.171926.
37. Kundu J, Michaelson A, Baranov P, et al. Approaches to cell delivery: substrates and scaffolds for cell therapy[J].Dev Ophthalmol,2014,53:143-154. DOI: 10.1159/000357369.
38. Song MJ, Bharti K. Looking into the future: using induced pluripotent stem cells to build two and three dimensional ocular tissue for cell therapy and disease modeling[J/OL]. Brain Res,2016,1598:E1[2015-12-17]. http://www.sciencedirect.com/science/article/pii/s0006899315009506.DOI: 10.1016/j.brainres.2015.12.011.[publisheaheadofprint].
39. Krishna Y, Sheridan C, Kent D, et al.Expanded polytetra-fluoroethylene as a substrate for retinal pigment epithelial cell growth and transplantation in age-related macular degeneration[J].Br J Ophthalmol, 2011,95(4):569-573.DOI: 10.1136/bjo.2009.169953.
40. Assawachananont J, Mandai M, Okamoto S,et al. Transplantation of embryonic and induced pluripotent stem cell-derived 3D retinal sheets into retinal degenerative mice[J]. Stem Cell Reports, 2014,2(5): 662-674.DOI:10.1016/j.stemcr.2014.03.011.
41. John S, Natarajan S, Parikumar P,et al. Choice of cell source in cell-based therapies for retinal damage due to age-related macular degeneration: a review[J/OL]. J Ophthalmol, 2013,2013:465169[2013-03-05].http://dx.doi.org/10.1155/2013/465169. DOI: 10.1155/2013/465169.
42. Fernández-Robredo P, Sancho A, Johnen S, et al. Current treatment limitations in age-related macular degeneration and future approaches based on cell therapy and tissue engineering[J/OL]. J Ophthalmol, 2014, 2014:510285 [2014-01-14]. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3941782/.DOI:10.1155/2014/510285.

Chinese Journal of Ocular Fundus Diseases

The progress of cell-replacement therapy for age-related macular degeneration

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