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Maeda, T. Stem Cell Therapies in AMD. Encyclopedia. Available online: https://encyclopedia.pub/entry/10256 (accessed on 24 June 2024).
Maeda T. Stem Cell Therapies in AMD. Encyclopedia. Available at: https://encyclopedia.pub/entry/10256. Accessed June 24, 2024.
Maeda, Tadao. "Stem Cell Therapies in AMD" Encyclopedia, https://encyclopedia.pub/entry/10256 (accessed June 24, 2024).
Maeda, T. (2021, May 29). Stem Cell Therapies in AMD. In Encyclopedia. https://encyclopedia.pub/entry/10256
Maeda, Tadao. "Stem Cell Therapies in AMD." Encyclopedia. Web. 29 May, 2021.
Stem Cell Therapies in AMD
Edit

Age-related macular degeneration (AMD) is a highly prevalent irreversible impairment in the elderly population worldwide. Stem cell therapies have been considered potentially viable for treating AMD through the direct replacement of degenerated cells or secretion of trophic factors that facilitate the survival of existing cells. 

regenerative medicine retinal pigment epithelium iPS cell ES cell stem cell age-related macular degeneration clinical trial retina immune reaction transplantation

1. Introduction

Age-related macular degeneration (AMD) is one of the most common causes of blindness worldwide, especially in the elderly population. As the global prevalence is 8.7% and the age of onset varying from 45 to 86 years, it is estimated to affect approximately 288 million individuals in western countries by 2040 [1]. Given the diverse variations among ethnicities, AMD is 10 times more prevalent among Caucasians compared to African-Americans. The early stages of AMD are characterized by the hallmarks, known as drusen and depigmentation of the retinal pigment epithelium (RPE) cells. Its progression from early to intermediate and advanced levels is driven by the increase in the numbers of drusen and degenerated RPE cells, resulting in pigmentary changes and the formation of choroidal neovascularization (CNV). The advanced stages of AMD are categorized into two forms: Non-neovascular (dry, non-exudative, or geographic) and neovascular (wet or exudative). Dry AMD is characterized by geographic atrophy of the RPE, photoreceptor, and choriocapillaris, resulting in gradual retinal cell loss and decreased visual acuity. In the wet-type AMD, CNV causes sub-retinal leakage of blood, lipids, fluids, and the formation of fibrous scars. Currently, AMD patients are recommended to receive routine medical management, including antioxidant supplements and anti-vascular endothelial growth factor (anti-VEGF) agents. The former, including vitamins, lutein, and zeaxanthin, are applied to protect the retinal cells from oxidative stress. Meanwhile, intravitreal injection of anti-VEGF agents, such as ranibizumab, aflibercept, and bevacizumab, which bind to VEGF receptors to block VEGF, is commonly used for treating wet-type AMD. However, current treatments do not target the underlying degeneration inherent in the disease, leading to a high recurrence rate upon the discontinuation of treatment. Furthermore, there are currently no effective methods for treating dry-type AMD. To address these problems, retinal cell therapy has attracted worldwide attention as the new era of treatment for retinal degenerative diseases [2][3][4][5], such as reconstruction and functional recovery of RPE by cell transplantation to maintain or restore visual function.
Currently, there are two types of formulations used for the administration of RPE cell products, namely, cell sheets with or without scaffolds and cell suspensions. In the case of RPE cell sheet transplantation, various dedicated devices have been used in previous publications [2][6][7][8]. Meanwhile, a soft-tip sub-retinal cannula is used for transplanting an RPE cell suspension [2][9][10][11]. Generally, the risk of surgical complications of RPE sheet transplantation is higher than RPE cell suspension due to the greater surgical invasiveness, involving a wider incision site and occasional removal of CNV before RPE sheet transplantation. The safety results of the transplantation of pluripotent stem cell-derived retinal pigment epithelial cells (RPE) in both formulations have been described in previous literature [6][7][8][9][10][11][12][13][14][15].
The conceptual mode of action of pluripotent stem cell-derived RPE cells for wet-type AMD (A) and dry-type AMD (B) in either formulation, RPE cell sheet, or RPE cell suspension were shown, respectively.

2. History of RPE Cell Therapy for Age-Related Macular Degeneration

Research on RPE cell transplantation began attracting attention in the late 1980s. Transplanting human RPE cells into a monkeys’ sub-retinal space revealed engraftment on Bruch’s membrane [16]. Since then, several reports have been published on the protective effect of RPE cell transplantation on the neural retina in animal models [2], demonstrating the possibility of securing materials for photoreceptor cells and RPE for use in the cell therapy of diseases with impaired retinal outer layer. Additionally, a proof of concept for treatment was obtained for the RPE.
In humans, Peyman first reported RPE transplantation in patients with AMD in 1991 [17]. In the first case, autologous cell transplantation was performed after removing the proliferative tissue under the macula. The nearby RPE was then transplanted into the macula to improve visual acuity. In the second case, the RPE was exfoliated from the donor’s eye as a sheet before being transplanted, but no visual acuity improvement was observed. The AMD-related CNV was removed, and a cell sheet obtained by culturing fetal-derived RPE was transplanted [18][19], but immune rejection occurred after the operation. Weisz also attempted injecting the fetal RPE as a cell suspension, but no improvement in the visual acuity was observed. Graft fibrosis was also observed [20]. Meanwhile, Del Priore transplanted a donor RPE sheet after removing the CNV, but the poor engraftment and visual acuity did not improve [21]. Almost all transplants using allografts in the eyes with a damaged blood-retinal barrier due to CNV removal showed rejection and deterioration in visual acuity.
Autologous transplantation is ideal for avoiding rejection. For some time, the RPE used for transplant was frequently collected from the peripheral area [22][23][24]. Although some patients had improved visual acuity, it was difficult to collect a sufficient number of autologous RPE cells with stable quality, and serious adverse events frequently occurred due to surgical invasion. In addition, among patients transplanted with peripheral RPE patches with the choroid, some resulted in improved visual acuity, but the surgical procedure had a higher risk of lacerating the patches. Furthermore, the choroid acted as a fibrous tissue if it was not connected to the host choroidal vessels.
As a countermeasure to these problems, the transplanted cell source was reviewed, and we reported RPE cells derived from pluripotent stem cells (ES cells, iPS cells) as candidate graft cells [25][26][27]. RPE cells derived from ES and iPS cells have the same functions as those derived from living organisms, and these cells form cell sheets through the collection of elegant hexagonal cells with tight junctions. Due to their easier preparation compared to primary cultured RPE cells, these have made dramatic developments in the cell therapy for AMD. Furthermore, RPE cell transplantation advanced first among the pluripotent stem cells due to the following characteristics of ES/iPS cell-derived RPE cells, making them more suitable for clinical application: (1) They have the required functions (quality), (2) the retina requires a small number of cells so that enough can be manufactured for transplantation (amount), (3) cells with certified quality for clinical use can always be obtained (reproducibility), and (4) the standard of purity was satisfied because of the color (purity). Furthermore, sub-retinal surgeries, such as CNV removal, have already been performed in the past. Thus, as described above, the field of ophthalmology has contributed greatly to the clinical application of pluripotent stem cells.

3. Cell Therapy for Age-Related Macular Degeneration Using Pluripotent Stem Cell-Derived RPE Cells

This section describes the implementation status of clinical studies on pluripotent stem cells in terms of the raw materials and the dosage form of the final product. The mode of action of cell therapy using pluripotent stem cell-derived RPE cells is shown in Figure 1, and a summary of clinical trials using pluripotent stem cell-derived RPE cells, with an updated status as of 31 December 2020 is presented in Table 1.
Figure 1. A conceptual mode of action of cell therapy using pluripotent stem cell-derived RPE cell products.
Table 1. Stem cell therapies for AMD with pluripotent stem cell derived-RPE.

No.

Study Title

Sponsor/Collaborators

Intervention

Age

Phases

No. of Subjects

Start/Completion Date

Status

Study ID

1

A Study of transplantation of autologous induced pluripotent stem cell (iPSC) derived retinal pigment epithelium (RPE) cell sheet in subjects with exudative age-related macular degeneration

the Laboratory for Retinal Regeneration, RIKEN Center for Developmental Biology

autologous hiPSC derived RPE cell sheet

50 years and older

P1

1

October 2013

/September 2018

completed

UMIN000011929

2

Autologous Transplantation of Induced Pluripotent Stem Cell-Derived Retinal Pigment Epithelium for Geographic Atrophy Associated With Age-Related Macular Degeneration

National Institutes of Health Clinical Center, Bethesda, Maryland, U.S.

Combination Product: hiPSC-derived RPE/PLGA scaffold

55 years and older

P1

20

July 2020

/March 2029

Recruiting

NCT04339764

3

A Study Of Implantation Of Retinal Pigment Epithelium In Subjects With Acute Wet Age Related Macular Degeneration

Moorfields Eye Hospital NHS Foundation Trust, London, U.K.

PF-05206388: RPE living tissue equivalent for intraocular use in the form of a monolayer of RPE cells immobilized on a polyester membrane.

60 years and older

P1

2

July 2020

/March 2029

Recruiting

NCT04339764

4

Study of Subretinal Implantation of Human Embryonic Stem Cell-Derived RPE Cells in Advanced Dry AMD

Retinal Arizona LTD, Phoenix, Arizona, U.S./Retina-Vitreous Associates Medical Group, Beverly Hills, California, U.S. and others

CPCB-RPE1 (Human Embryonic Stem Cell-Derived RPE Cells Seeded on a Polymeric Substrate)

55 years to 85 years

P1/2a

16

July 2019

/June 2023

Active, not recruiting

NCT02590692

5

A Study of transplantation of allogenic induced pluripotent stem cell (iPSC) derived retinal pigment epithelium (RPE) cell suspension in subjects with neovascular age related macular degeneration

the Laboratory for Retinal Regeneration, RIKEN Center for Developmental Biology, Kobe, Japan/ Kobe City Medical Center General Hosital, Kobe, Japan

Subretinal transplantation of allogenic hiPSC derived RPE cells

50 years to 85 years

P1

5

February 2017

/October 2021

Active, not recruiting

UMIN000026003

6

Stem Cell Therapy for Outer Retinal Degenerations

Federal University of Sao Paulo, Sao Paulo, Brazil

injection of hESC derived RPE in suspension/Procedure: injection hESC derived RPE seeded in a substrate

18 years to 90 years

P1/2

15

September 2016

/July 2020

Completed

NCT02903576

7

Subretinal Transplantation of Retinal Pigment Epitheliums in Treatment of Age-related Macular Degeneration Diseases

Chinese Academy of Sciences/Beijing Tongren Hospital, China

hESC derived RPE

55 years and older

P1/2

10

January 2018

/December 2020

Recruiting

NCT02755428

8

Safety and Efficacy of Subretinal Transplantation of Clinical Human Embryonic Stem Cell Derived Retinal Pigment Epitheliums in Treatment of Retinitis Pigmentosa

Qi Zhou, Chinese Academy of Sciences

hESC derived RPE

18 years and older

P1

10

May 2020

/December 2021

Recruiting

NCT03944239

9

Treatment of Dry Age Related Macular Degeneration Disease With Retinal Pigment Epithelium Derived From Human Embryonic Stem Cells

Chinese Academy of Sciences/ The First Affiliated Hospital of Zhengzhou University, China

hESC derived RPE

55 years and older

P1/2

15

September 2017

/December 2020

Recruiting

NCT03046407

10

Safety and Tolerability of Sub-retinal Transplantation of Human Embryonic Stem Cell Derived Retinal Pigmented Epithelial (hESC-RPE) Cells in Patients With Stargardt’s Macular Dystrophy (SMD)

Astellas Institute for Regenerative Medicine/Astellas Pharma Inc., U.S.

hESC derived RPE (MA09-hRPE)

18 years and older

P1/2

15

November 2011

/September 2015

completed

NCT01469832

11

A Follow up Study to Determine the Safety and Tolerability of Sub-retinal Transplantation of Human Embryonic Stem Cell Derived Retinal Pigmented Epithelial (hESC-RPE) Cells in Patients With Stargardt’s Macular Dystrophy (SMD)

Astellas Institute for Regenerative Medicine/Astellas Pharma Inc., U.S.

hESC derived RPE (MA09-hRPE)

18 years and older

 

12

January 2013

/October 2019

completed

NCT02941991

12

Sub-retinal Transplantation of hESC Derived RPE(MA09-hRPE) Cells in Patients With Stargardt’s Macular Dystrophy

Astellas Institute for Regenerative Medicine/Astellas Pharma Inc., U.S.

hESC derived RPE (MA09-hRPE)

18 years and older

P1/2

13

April 2011

/August 2015

completed

NCT01345006

13

Safety and Tolerability of Sub-retinal Transplantation of hESC Derived RPE (MA09-hRPE) Cells in Patients With Advanced Dry Age Related Macular Degeneration

Astellas Institute for Regenerative Medicine/Astellas Pharma Inc., U.S.

hESC derived RPE (MA09-hRPE)

55 years and older

P1/2

13

April 2011

/August 2015

completed

NCT01344993

14

Long Term Follow Up of Sub-retinal Transplantation of hESC Derived RPE Cells in Stargardt Macular Dystrophy Patients

Astellas Institute for Regenerative Medicine/Astellas Pharma Inc., U.S.

hESC derived RPE (MA09-hRPE)

18 years and older

P1

13

July 2012

/June 2019

completed

NCT02445612

15

Long Term Follow Up of Sub-retinal Transplantation of hESC Derived RPE Cells in Patients With AMD

Astellas Institute for Regenerative Medicine/Astellas Pharma Inc., U.S.

hESC derived RPE (MA09-hRPE)

18 years and older

 

11

February 2013

/August 2019

completed

NCT02463344

16

A Phase I/IIa, Open-Label, Single-Center, Prospective Study to Determine the Safety and Tolerability of Sub-retinal Transplantation of Human ES Cell Derived RPE (MA09-hRPE) Cells in Patients With Advanced Dry Age-related Macular Degeneration (AMD)

Astellas Institute for Regenerative Medicine/Astellas Pharma Inc., U.S.

hESC derived RPE (MA09-hRPE)

55 years and older

P1/2a

12

September 2012

/June 2020

Active, not recruiting

NCT01674829

17

A Safety Surveillance Study in Subjects With Macular Degenerative Disease Treated With Human Embryonic Stem Cell-derived Retinal Pigment Epithelial Cell Therapy

Astellas Institute for Regenerative Medicine/Astellas Pharma Inc., U.S.

hESC derived RPE (MA09-hRPE)

18 years and older

P1/2

36

January 2018

/December 2029

Enrolling by invitation

NCT03167203

18

Retinal Pigment Epithelium Safety Study For Patients In B4711001

Moorfields Eye Hospital NHS Foundation Trust, U.K.

hESC derived RPE

60 years and older

 

2

September 2016

/October 2020

Active, not recruiting

NCT03102138

19

Safety and Efficacy Study of OpRegen for Treatment of Advanced Dry-Form Age-Related Macular Degeneration

Lineage Cell Therapeutics, Inc./CellCure Neurosciences Ltd., Israel

OpRegen

50 years and older

P1/2

24

August 2015

/December 2024

Recruiting

NCT02286089

References

  1. Wong, W.L.; Su, X.; Li, B.X.; Cheung, C.M.G.; Klein, B.E.; Cheng, C.-Y.; Wong, T.Y. 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, e106–e116.
  2. Singh, M.S.; Park, S.S.; Albini, T.A.; Canto-Soler, M.V.; Klassen, H.; MacLaren, R.E.; Takahashi, M.; Nagiel, A.; Schwartz, S.D.; Bharti, K. Retinal stem cell transplantation: Balancing safety and potential. Prog. Retin. Eye Res. 2020, 75, 100779.
  3. Wang, Y.; Tang, Z.; Gu, P. Stem/progenitor cell-based transplantation for retinal degeneration: A review of clinical trials. Cell Death Dis. 2020, 11, 1–14.
  4. Maeda, A.; Mandai, M.; Takahashi, M. Gene and Induced Pluripotent Stem Cell Therapy for Retinal Diseases. Annu. Rev. Genom. Hum. Genet. 2019, 20, 201–216.
  5. Scholl, H.P.N.; Strauss, R.W.; Singh, M.S.; Dalkara, D.; Roska, B.; Picaud, S.; Sahel, J.-A. Emerging therapies for inherited retinal degeneration. Sci. Transl. Med. 2016, 8, 368rv6.
  6. Mandai, M.; Watanabe, A.; Kurimoto, Y.; Hirami, Y.; Morinaga, C.; Daimon, T.; Fujihara, M.; Akimaru, H.; Sakai, N.; Shibata, Y.; et al. Autologous Induced Stem-Cell–Derived Retinal Cells for Macular Degeneration. N. Engl. J. Med. 2017, 376, 1038–1046.
  7. Da Cruz, L.; Fynes, K.; Georgiadis, O.; Kerby, J.; Luo, Y.H.; Ahmado, A.; Vernon, A.; Daniels, J.T.; Nommiste, B.; Hasan, S.M.; 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, 328–337.
  8. Kashani, A.H.; Lebkowski, J.S.; Rahhal, F.M.; Avery, R.L.; Salehi-Had, H.; Dang, W.; Lin, C.-M.; Mitra, D.; Zhu, D.; Thomas, B.B.; et al. A bioengineered retinal pigment epithelial monolayer for advanced, dry age-related macular degeneration. Sci. Transl. Med. 2018, 10, eaao4097.
  9. Sugita, S.; Mandai, M.; Hirami, Y.; Takagi, S.; Maeda, T.; Fujihara, M.; Matsuzaki, M.; Yamamoto, M.; Iseki, K.; Hayashi, N.; et al. HLA-Matched Allogeneic iPS Cells-Derived RPE Transplantation for Macular Degeneration. J. Clin. Med. 2020, 9, 2217.
  10. Schwartz, S.D.; Regillo, C.D.; Lam, B.L.; Eliott, D.; Rosenfeld, P.J.; Gregori, N.Z.; Hubschman, J.-P.; Davis, J.L.; Heilwell, G.; Spirn, M.; 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, 509–516.
  11. Schwartz, S.D.; Hubschman, J.-P.; Heilwell, G.; Franco-Cardenas, V.; Pan, C.K.; Ostrick, R.M.; Mickunas, E.; Gay, R.; Klimanskaya, I.; Lanza, R. Embryonic stem cell trials for macular degeneration: A preliminary report. Lancet 2012, 379, 713–720.
  12. Takagi, S.; Mandai, M.; Gocho, K.; Hirami, Y.; Yamamoto, M.; Fujihara, M.; Sugita, S.; Kurimoto, Y.; Takahashi, M. Evaluation of Transplanted Autologous Induced Pluripotent Stem Cell-Derived Retinal Pigment Epithelium in Exudative Age-Related Macular Degeneration. Ophthalmol. Retin. 2019, 3, 850–859.
  13. Mehat, M.S.; Sundaram, V.; Ripamonti, C.; Robson, A.G.; Smith, A.J.; Borooah, S.; Robinson, M.; Rosenthal, A.N.; Innes, W.; Weleber, R.G.; et al. Transplantation of Human Embryonic Stem Cell-Derived Retinal Pigment Epithelial Cells in Macular Degeneration. Ophthalmology 2018, 125, 1765–1775.
  14. Sung, Y.; Lee, M.J.; Choi, J.; Jung, S.Y.; Chong, S.Y.; Sung, J.H.; Shim, S.H.; Song, W.K. Long-term safety and tolerability of subretinal transplantation of embryonic stem cell-derived retinal pigment epithelium in Asian Stargardt disease patients. Br. J. Ophthalmol. 2020, 10, 1136.
  15. Song, W.K.; Park, K.-M.; Kim, H.-J.; Lee, J.H.; Choi, J.; Chong, S.Y.; Shim, S.H.; Del Priore, L.V.; Lanza, R. Treatment of Macular Degeneration Using Embryonic Stem Cell-Derived Retinal Pigment Epithelium: Preliminary Results in Asian Patients. Stem Cell Rep. 2015, 4, 860–872.
  16. Gouras, P.; Flood, M.T.; Kjeldbye, H.; Bilek, M.K.; Eggers, H. Transplantation of cultured human retinal epithelium to Bruch’s membrane of the owl monkey’s eye. Curr. Eye Res. 1985, 4, 253–265.
  17. Peyman, A.G.; Blinder, K.J.; Paris, C.L.; Alturki, W.; Nelson, J.N.C.; Desai, U. A Technique for Retinal Pigment Epithelium Transplantation for Age-Related Macular Degeneration Secondary to Extensive Subfoveal Scarring. Ophthalmic Surg. Lasers Imaging Retin. 1991, 22, 102–108.
  18. Algvere, P.V.; Berglin, L.; Gouras, P.; Sheng, Y. Transplantation of fetal retinal pigment epithelium in age-related macular degeneration with subfoveal neovascularization. Graefe’s Arch. Clin. Exp. Ophthalmol. 1994, 232, 707–716.
  19. Algvere, P.V.; Berglin, L.; Gouras, P.; Sheng, Y. Transplantation of RPE in age-related macular degeneration: Observations in disciform lesions and dry RPE atrophy. Graefe’s Arch. Clin. Exp. Ophthalmol. 1997, 235, 149–158.
  20. Weisz, J.M.; Humayun, M.S.; De Juan, E.; Del Cerro, M.; Sunness, J.S.; Dagnelie, G.; Soylu, M.; Rizzo, L.; Nussenblatt, R.B. Allogenic fetal retinal pigment epithelial cell transplant in a patient with geographic atrophy. Retina 1999, 19, 540–545.
  21. Del Priore, L.V.; Kaplan, H.J.; Tezel, T.H.; Hayashi, N.; Berger, A.S.; Green, W. Retinal pigment epithelial cell transplantation after subfoveal membranectomy in age-related macular degeneration. Am. J. Ophthalmol. 2001, 131, 472–480.
  22. Joussen, A.M.; Heussen, F.M.; Joeres, S.; Llacer, H.; Prinz, B.; Rohrschneider, K.; Maaijwee, K.J.; Van Meurs, J.; Kirchhof, B. Autologous Translocation of the Choroid and Retinal Pigment Epithelium in Age-related Macular Degeneration. Am. J. Ophthalmol. 2006, 142, 17–30.
  23. MacLaren, R.E.; Uppal, G.S.; Balaggan, K.S.; Tufail, A.; Munro, P.M.; Milliken, A.B.; Ali, R.R.; Rubin, G.S.; Aylward, G.W.; Da Cruz, L. Autologous Transplantation of the Retinal Pigment Epithelium and Choroid in the Treatment of Neovascular Age-Related Macular Degeneration. Ophthalmology 2007, 114, 561–570.
  24. Maaijwee, K.; Heimann, H.; Missotten, T.; Mulder, P.; Joussen, A.; Van Meurs, J. Retinal pigment epithelium and choroid translocation in patients with exudative age-related macular degeneration: Long-term results. Graefe’s Arch. Clin. Exp. Ophthalmol. 2007, 245, 1681–1689.
  25. Haruta, M.; Sasai, Y.; Kawasaki, H.; Amemiya, K.; Ooto, S.; Kitada, M.; Suemori, H.; Nakatsuji, N.; Ide, C.; Honda, Y.; et al. In vitro and in vivo characterization of pigment epithelial cells differentiated from primate embryonic stem cells. Investig. Opthalmol. Vis. Sci. 2004, 45, 1020–1025.
  26. Osakada, F.; Ikeda, H.; Sasai, Y.; Takahashi, M. Stepwise differentiation of pluripotent stem cells into retinal cells. Nat. Protoc. 2009, 4, 811–824.
  27. Hirami, Y.; Osakada, F.; Takahashi, K.; Okita, K.; Yamanaka, S.; Ikeda, H.; Yoshimura, N.; Takahashi, M. Generation of retinal cells from mouse and human induced pluripotent stem cells. Neurosci. Lett. 2009, 458, 126–131.
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