Advancing a Stem Cell Therapy for Age-Related Macular Degeneration

Author(s): Helen C. O’Neill*, Ioannis J. Limnios, Nigel L. Barnett

Journal Name: Current Stem Cell Research & Therapy

Volume 15 , Issue 2 , 2020

Become EABM
Become Reviewer
Call for Editor


The retinal pigment epithelium (RPE) is a multifunctional monolayer located at the back of the eye required for the survival and function of the light-sensing photoreceptors. In Age-related Macular Degeneration (AMD), the loss of RPE cells leads to photoreceptor death and permanent blindness. RPE cell transplantation aims to halt or reverse vision loss by preventing the death of photoreceptor cells and is considered one of the most viable applications of stem cell therapy in the field of regenerative medicine. Proof-of-concept of RPE cell transplantation for treating retinal degenerative disease, such as AMD, has long been established in animal models and humans using primary RPE cells, while recent research has focused on the transplantation of RPE cells derived from human pluripotent stem cells (hPSC). Early results from clinical trials indicate that transplantation of hPSC-derived RPE cells is safe and can improve vision in AMD patients. Current hPSC-RPE cell production protocols used in clinical trials are nevertheless inefficient. Treatment of large numbers of AMD patients using stem cellderived products may be dependent on the ability to generate functional cells from multiple hPSC lines using robust and clinically-compliant methods. Transplantation outcomes may be improved by delivering RPE cells on a thin porous membrane for better integration into the retina, and by manipulation of the outcome through control of immune rejection and inflammatory responses.

Keywords: Pluripotent stem cells, retinal pigment epithelium, age-related macular degeneration, cell transplantation, stem cell therapy.

Wong WL, Su X, Li X, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: A systematic review and meta-analysis. Lancet Glob Health 2014; 2(2): e106-16.
[] [PMID: 25104651]
da Cruz L, Fynes K, Georgiadis O, et al. Phase 1 clinical study of an embryonic stem cell-derived retinal pigment epithelium patch in age-related macular degeneration. Nat Biotechnol 2018; 36(4): 328-37.
[] [PMID: 29553577]
Kashani AH, Lebkowski JS, Rahhal FM, et al. A bioengineered retinal pigment epithelial monolayer for advanced, dry age-related macular degeneration. Sci Transl Med 2018; 10(435)eaa04097
[] [PMID: 29618560]
Mandai M, Watanabe A, Kurimoto Y, et al. Autologous induced stem-cell-derived retinal cells for macular degeneration. N Engl J Med 2017; 376(11): 1038-46.
[] [PMID: 28296613]
Surrao DC, Greferath U, Chau YQ, et al. Design, development and characterization of synthetic Bruch’s membranes. Acta Biomater 2017; 64: 357-76.
[] [PMID: 28951331]
Surrao D, Skabo S, Chau YQ, Limnios IJ, Shelat K, Liu Q. Design, development and in vitro evaluation of synthetic scaffolds for retinal tissue engineering. Front Bioeng Biotechnol 2016; 4.
Buchholz DE, Pennington BO, Croze RH, Hinman CR, Coffey PJ, Clegg DO. Rapid and efficient directed differentiation of human pluripotent stem cells into retinal pigmented epithelium. Stem Cells Transl Med 2013; 2(5): 384-93.
[] [PMID: 23599499]
Foltz LP, Clegg DO. Rapid, directed differentiation of retinal pigment epithelial cells from human embryonic or induced pluripotent stem cells. J Vis Exp 2017; (128):
[] [PMID: 29155780]
Idelson M, Alper R, Obolensky A, et al. Directed differentiation of human embryonic stem cells into functional retinal pigment epithelium cells. Cell Stem Cell 2009; 5(4): 396-408.
[] [PMID: 19796620]
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. (Brain Res.)2016; 1638(Pt A): 2-14.
[] [PMID: 26706569]
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(11): 4151-60.
[] [PMID: 15505069]
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. Br J Ophthalmol 2011; 95(3): 370-5.
[] [PMID: 20610478]
Radtke ND, Aramant RB, Petry HM, Green PT, Pidwell DJ, Seiler MJ. Vision improvement in retinal degeneration patients by implantation of retina together with retinal pigment epithelium. Am J Ophthalmol 2008; 146(2): 172-82.
[] [PMID: 18547537]
Bobba S, Di Girolamo N, Munsie M, et al. The current state of stem cell therapy for ocular disease. Exp Eye Res 2018; 177: 65-75.
[] [PMID: 30029023]
Nazari H, Zhang L, Zhu D, et al. Stem cell based therapies for age-related macular degeneration: The promises and the challenges. Prog Retin Eye Res 2015; 48: 1-39.
[] [PMID: 26113213]
Haruta M, Sasai Y, Kawasaki H, et al. In vitro and in vivo characterization of pigment epithelial cells differentiated from primate embryonic stem cells. Invest Ophthalmol Vis Sci 2004; 45(3): 1020-5.
[] [PMID: 14985325]
Kawasaki H, Suemori H, Mizuseki K, et al. Generation of dopaminergic neurons and pigmented epithelia from primate ES cells by stromal cell-derived inducing activity. Proc Natl Acad Sci USA 2002; 99(3): 1580-5.
[] [PMID: 11818560]
Mehat MS, Sundaram V, Ripamonti C, et al. Transplantation of human embryonic stem cell-derived retinal pigment epithelial cells in macular degeneration. Ophthalmology 2018; 125(11): 1765-75.
[] [PMID: 29884405]
Vugler A, Carr AJ, Lawrence J, et al. Elucidating the phenomenon of HESC-derived RPE: anatomy of cell genesis, expansion and retinal transplantation. Exp Neurol 2008; 214(2): 347-61.
[] [PMID: 18926821]
Idelson M, Alper R, Obolensky A, et al. Immunological properties of human embryonic stem cell-derived retinal pigment epithelial cells. Stem Cell Reports 2018; 11(3): 681-95.
[] [PMID: 30122442]
Limnios IJ. Methods for differentiating cells. In: International Patent Application NoPCT/AU2016/000390. International Publication No WO2017/091844.. 2017. published June 8, 2017.
Lu B, Malcuit C, Wang S, et al. Long-term safety and function of RPE from human embryonic stem cells in preclinical models of macular degeneration. In: Stem cells [Dayton, Ohio]. 2009; 27: pp. (9)2126-35.
[] [PMID: 19521979]
Maminishkis A, Miller SS. Experimental models for study of retinal pigment epithelial physiology and pathophysiology. J Vis Exp 2010; 45(45): 3032.
[] [PMID: 21085105]
Schwartz SD, Hubschman JP, Heilwell G, et al. Embryonic stem cell trials for macular degeneration: a preliminary report. Lancet 2012; 379(9817): 713-20.
[] [PMID: 22281388]
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. Lancet 2015; 385(9967): 509-16.
[] [PMID: 25458728]
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. Stem Cell Reports 2015; 4(5): 860-72.
[] [PMID: 25937371]
Sharma R, Khristov V, Rising A, et al. Clinical-grade stem cell-derived retinal pigment epithelium patch rescues retinal degeneration in rodents and pigs. Sci Transl Med 2019; 11(475)eaat5580
[] [PMID: 30651323]
Stanzel BV, Liu Z, Somboonthanakij S, et al. Human RPE stem cells grown into polarized RPE monolayers on a polyester matrix are maintained after grafting into rabbit subretinal space. Stem Cell Reports 2014; 2(1): 64-77.
[] [PMID: 24511471]
Thomas BB, Zhu D, Zhang L, et al. Survival and functionality of hESC-derived retinal pigment epithelium cells cultured as a monolayer on polymer substrates transplanted in RCS rats. Invest Ophthalmol Vis Sci 2016; 57(6): 2877-87.
[] [PMID: 27233037]
Diniz B, Thomas P, Thomas B, et al. Subretinal implantation of retinal pigment epithelial cells derived from human embryonic stem cells: improved survival when implanted as a monolayer. Invest Ophthalmol Vis Sci 2013; 54(7): 5087-96.
[] [PMID: 23833067]
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. Stem Cell Reports 2014; 2(2): 205-18.
[] [PMID: 24527394]
Warnke PH, Liu Q. Bond University Ltd. Customised compositions and uses thereof. US Patent No 9,095,524 B2 US Publication No 2013/0095167 A1 2013. published Apr 18, 2013..
Holtkamp GM, Kijlstra A, Peek R, de Vos AF. Retinal pigment epithelium-immune system interactions: Cytokine production and cytokine-induced changes. Prog Retin Eye Res 2001; 20(1): 29-48.
[] [PMID: 11070367]
Zhao T, Zhang ZN, Westenskow PD, et al. Humanized mice reveal differential immunogenicity of cells derived from autologous induced pluripotent stem cells. Cell Stem Cell 2015; 17(3): 353-9.
[] [PMID: 26299572]
Sugita S, Kamao H, Iwasaki Y, et al. Inhibition of T-cell activation by retinal pigment epithelial cells derived from induced pluripotent stem cells. Invest Ophthalmol Vis Sci 2015; 56(2): 1051-62.
[] [PMID: 25604685]
Karabekian Z, Ding H, Stybayeva G, et al. HLA class I depleted hESC as a source of hypoimmunogenic cells for tissue engineering applications. Tissue Eng Part A 2015; 21(19-20): 2559-71.
[] [PMID: 26218149]
Pappas DJ, Gourraud PA, Le Gall C, et al. Proceedings: Human leukocyte antigen haplo-homozygous induced pluripotent stem cell haplobank modeled after the california population: evaluating matching in a multiethnic and admixed population. Stem Cells Transl Med 2015; 4(5): 413-8.
[] [PMID: 25926330]
Nakajima F, Tokunaga K, Nakatsuji N. Human leukocyte antigen matching estimations in a hypothetical bank of human embryonic stem cell lines in the Japanese population for use in cell transplantation therapy. Stem Cells 2007; 25(4): 983-5.
[] [PMID: 17185611]
Kanemura H, Go MJ, Shikamura M, et al. Tumorigenicity studies of induced pluripotent stem cell (iPSC)-derived retinal pigment epithelium (RPE) for the treatment of age-related macular degeneration. PLoS One 2014; 9(1)e85336
[] [PMID: 24454843]
Warnke PH, Alamein M, Skabo S, et al. Primordium of an artificial Bruch’s membrane made of nanofibers for engineering of retinal pigment epithelium cell monolayers. Acta Biomater 2013; 9(12): 9414-22.
[] [PMID: 23917149]
Okunuki Y, Mukai R, Pearsall EA, et al. Microglia inhibit photoreceptor cell death and regulate immune cell infiltration in response to retinal detachment. Proc Natl Acad Sci USA 2018; 115(27): E6264-73.
[] [PMID: 29915052]
Osakada F, Jin ZB, Hirami Y, et al. In vitro differentiation of retinal cells from human pluripotent stem cells by small-molecule induction. J Cell Sci 2009; 122(Pt 17): 3169-79.
[] [PMID: 19671662]

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2020
Published on: 26 March, 2020
Page: [89 - 97]
Pages: 9
DOI: 10.2174/1574888X15666191218094020

Article Metrics

PDF: 48
HTML: 18
PRC: 1