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Moghadam Fard A, Mirshahi R, Naseripour M, Ghasemi Falavarjani K. Stem Cell Therapy in Stargardt Disease: A Systematic Review. JOVR [Internet]. 2023Jul.23 [cited 2024May15];18(3):318–327. Available from: https://knepublishing.com/index.php/JOVR/article/view/13780
https://doi.org/10.18502/jovr.v18i3.13780
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authors
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Atousa Moghadam Fard
Atousa Moghadam Fard
Eye Research Center, The Five Senses Health Institute, Rassoul Akram Hospital, Iran University of Medical Sciences, Tehran, Iran
-
Reza Mirshahi
Reza Mirshahi
Eye Research Center, The Five Senses Health Institute, Rassoul Akram Hospital, Iran University of Medical Sciences, Tehran, Iran
-
Masood Naseripour
Masood Naseripour
Stem Cell and Regenerative Medicine Research Center, Iran University of Medical Sciences, Tehran, Iran
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Khalil Ghasemi Falavarjani
Khalil Ghasemi Falavarjani
Stem Cell and Regenerative Medicine Research Center, Iran University of Medical Sciences, Tehran, Iran
Published Date
- Jul 23, 2023
Stem Cell Therapy in Stargardt Disease: A Systematic Review
Abstract
This article aimed to review current literature on the safety and efficacy of stem cell therapy in Stargardt disease. A comprehensive literature search was performed, and two animal and eleven human clinical trials were retrieved. These studies utilized different kinds of stem cells, including human or mouse embryonic stem cells, mesenchymal stem cells, bone marrow mononuclear fraction, and autologous bone marrow-derived stem cells. In addition, different injection techniques including subretinal, intravitreal, and suprachoroidal space injections have been evaluated. Although stem cell therapy holds promise in improving visual function in patients with Stargardt disease, further investigation is needed to determine the long-term benefits, safety, and efficacy in determining the best delivery method and selecting the most appropriate stem cell type.
Keywords:
Juvenile-Onset Macular Degeneration; Juvenile-Onset Macular Dystrophy; Stargardt Disease; Stem Cell; Stem Cell Therapy
References
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9. Hussain RM, Ciulla TA, Berrocal AM, Gregori NZ, Flynn HW Jr, Lam BL. Stargardt macular dystrophy and evolving therapies. Expert Opin Biol Ther 2018;18:1049–1059.
10. Battu R, Ratra D, Gopal L. Newer therapeutic options for inherited retinal diseases: Gene and cell replacement therapy. Indian J Ophthalmol 2022;70:2316–2325.
11. Strauss RW, Ho A, Muñoz B, Cideciyan AV, Sahel JA, Sunness JS, et al. The natural history of the progression of atrophy secondary to Stargardt Disease (ProgStar) Studies: Design and baseline characteristics: ProgStar report no.1. Ophthalmology 2016;123:817–828.
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24. Wert KJ, Skeie JM, Davis RJ, Tsang SH, Mahajan VB. Subretinal injection of gene therapy vectors and stem cells in the perinatal mouse eye. J Vis Exp 2012;69:4286.
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26. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ 2021;372:n71.
27. Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, et al. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. J Clin Epidemiol 2011;64:383–394.
28. Heath Jeffery RC, Chen FK. Stargardt disease: Multimodal imaging: A review. Clin Exp Ophthalmol 2021;49:498–515.
29. Walia S, Fishman GA. Natural history of phenotypic changes in Stargardt macular dystrophy. Ophthalmic Genet 2009;30:63–68.
30. Palejwala NV, Gale MJ, Clark RF, Schlechter C, Weleber RG, Pennesi ME. Insights into autosomal dominant Stargardt-like macular dystrophy through multimodality diagnostic imaging. Retina 2016;36:119–130.
31. Donoso LA, Edwards AO, Frost A, Vrabec T, Stone EM, Hageman GS, et al. Autosomal dominant Stargardt-like macular dystrophy. Surv Ophthalmol 2001;46:149–163.
32. Vasireddy V, Wong P, Ayyagari R. Genetics and molecular pathology of Stargardt-like macular degeneration. Prog Retin Eye Res 2010;29:191–207.
33. Schulz HL, Grassmann F, Kellner U, Spital G, Rüther K, Jägle H, et al. Mutation spectrum of the ABCA4 gene in 335 Stargardt disease patients from a multicenter german cohort-impact of selected deep intronic variants and common SNPs. Invest Ophthalmol Vis Sci 2017;58:394– 403.
34. Tsybovsky Y, Molday RS, Palczewski K. The ATP-binding cassette transporter ABCA4: Structural and functional properties and role in retinal disease. Adv Exp Med Biol 2010;703:105–125.
35. Lu LJ, Liu J, Adelman RA. Novel therapeutics for Stargardt disease. Graefes Arch Clin Exp Ophthalmol 2017;255:1057–1062.
36. Sparrow JR, Boulton M. RPE lipofuscin and its role in retinal pathobiology. Exp Eye Res 2005;80:595–606.
37. Parmar VM, Parmar T, Arai E, Perusek L, Maeda A. A2E-associated cell death and inflammation in retinal pigmented epithelial cells from human induced pluripotent stem cells. Stem Cell Res 2018;27:95–104.
38. Ng ES, Kady N, Hu J, Dave A, Jiang Z, Pei J, et al. Membrane attack complex mediates retinal pigment epithelium cell death in Stargardt macular degeneration. Cells 2022;11:3462.
39. Tanna P, Strauss RW, Fujinami K, Michaelides M. Stargardt disease: Clinical features, molecular genetics, animal models and therapeutic options. Br J Ophthalmol 2017;101:25–30.
40. Chen Y, Okano K, Maeda T, Chauhan V, Golczak M, Maeda A, et al. Mechanism of all-trans-retinal toxicity with implications for Stargardt disease and age-related macular degeneration. J Biol Chem 2012;287:5059–5069.
41. Radu RA, Mata NL, Bagla A, Travis GH. Light exposure stimulates formation of A2E oxiranes in a mouse model of Stargardt’s macular degeneration. Proc Natl Acad Sci USA 2004;101:5928–5933.
42. Teussink MM, Lee MD, Smith RT, van Huet RA, Klaver CC, Klevering BJ, et al. The effect of light deprivation in patients with Stargardt disease. Am J Ophthalmol 2015;159:964–972.e2.
43. Fujinami K, Strauss RW, Chiang JP, Audo IS, Bernstein PS, Birch DG, et al. Detailed genetic characteristics of an international large cohort of patients with Stargardt disease: ProgStar study report 8. Br J Ophthalmol 2019;103:390–397.
44. Lee W, Xie Y, Zernant J, Yuan B, Bearelly S, Tsang SH, et al. Complex inheritance of ABCA4 disease: Four mutations in a family with multiple macular phenotypes. Hum Genet 2016;135:9–19.
45. Arrigo A, Grazioli A, Romano F, Aragona E, Bordato A, di Nunzio C, et al. Choroidal patterns in Stargardt disease: Correlations with visual acuity and disease progression. J Clin Med 2019;8:1388.
46. Collison FT, Fishman GA. Visual acuity in patients with Stargardt disease after age 40. Retina 2018;38:2387– 2394.
47. Fujinami K, Zernant J, Chana RK, Wright GA, Tsunoda K, Ozawa Y, et al. ABCA4 gene screening by next-generation sequencing in a British cohort. Invest Ophthalmol Vis Sci 2013;54:6662–6674.
48. Lambertus S, van Huet RA, Bax NM, Hoefsloot LH, Cremers FP, Boon CJ, et al. Early-onset Stargardt disease: Phenotypic and genotypic characteristics. Ophthalmology 2015;122:335–344.
49. Fujinami K, Zernant J, Chana RK, Wright GA, Tsunoda K, Ozawa Y, et al. Clinical and molecular characteristics of childhood-onset Stargardt disease. Ophthalmology 2015;122:326–334.
50. Ramsden CM, Powner MB, Carr AJ, Smart MJ, da Cruz L, Coffey PJ. Stem cells in retinal regeneration: Past, present and future. Development 2013;140:2576–2585.
51. Araki R, Uda M, Hoki Y, Sunayama M, Nakamura M, Ando S, et al. Negligible immunogenicity of terminally differentiated cells derived from induced pluripotent or embryonic stem cells. Nature 2013;494:100–104.
52. Mead B, Berry M, Logan A, Scott RA, Leadbeater W, Scheven BA. Stem cell treatment of degenerative eye disease. Stem Cell Res 2015;14:243–257.
53. 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.
54. Ahmed I, Johnston RJ Jr, Singh MS. Pluripotent stem cell therapy for retinal diseases. Ann Transl Med 2021;9:1279.
55. Maeda A, Mandai M, Takahashi M. Gene and induced pluripotent stem cell therapy for retinal diseases. Annu Rev Genomics Hum Genet 2019;20:201–216.
56. Han F, Xu G. Stem cell transplantation therapy for retinal degenerative diseases. Adv Exp Med Biol 2020;1266:127– 139.
57. Sharma A, Jaganathan BG. Stem cell therapy for retinal degeneration: The evidence to date. Biologics 2021;15:299–306.
58. Ding DC, Shyu WC, Lin SZ. Mesenchymal stem cells. Cell Transplant 2011;20:5–14.
59. Fu X, Liu G, Halim A, Ju Y, Luo Q, Song AG. Mesenchymal stem cell migration and tissue repair. Cells 2019;8:784.
60. Lin Y, Ren X, Chen Y, Chen D. Interaction between mesenchymal stem cells and retinal degenerative microenvironment. Front Neurosci 2021;14:617377.
61. Xian B, Huang B. The immune response of stem cells in subretinal transplantation. Stem Cell Res Ther 2015;6:161.
62. Streilein JW, Ma N, Wenkel H, Ng TF, Zamiri P. Immunobiology and privilege of neuronal retina and pigment epithelium transplants. Vision Res 2002;42:487– 495.
63. Sugita S, Horie S, Nakamura O, Maruyama K, Takase H, Usui Y. Acquisition of T regulatory function in cathepsin L-inhibited T cells by eye-derived CTLA-2alpha during inflammatory conditions. J Immunol 2009;183:5013–5022.
64. Raimondi R, Zollet P, De Rosa FP, Tsoutsanis P, Stravalaci M, Paulis M, et al. Where are we with RPE replacement therapy? A translational review from the ophthalmologist perspective. Int J Mol Sci 2022;23:682.
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2. Stone EM, Andorf JL, Whitmore SS, DeLuca AP, Giacalone JC, Streb LM, et al. Clinically focused molecular investigation of 1000 consecutive families with inherited retinal disease. Ophthalmology 2017;124:1314–1331.
3. Haddley K. Stargardt disease: Light at the end of the tunnel. Drugs Future 2011;36:527–533.
4. Sears AE, Bernstein PS, Cideciyan AV, Hoyng C, Charbel Issa P, Palczewski K, et al. Towards treatment of Stargardt disease: Workshop organized and sponsored by the foundation fighting blindness. Transl Vis Sci Technol 2017;6:6.
5. Haji Abdollahi S, Hirose T. Stargardt-Fundus flavimaculatus: Recent advancements and treatment. Semin Ophthalmol 2013;28:372–376.
6. Khan M, Cremers FP. ABCA4-associated Stargardt disease. Klin Monatsbl Augenheilkd 2020;237:267–274.
7. Jonsson F, Westin IM, Österman L, Sandgren O, Burstedt M, Holmberg M, et al. ATP-binding cassette subfamily A, member 4 intronic variants c.4773+3A>G and c.5461- 10T>C cause Stargardt disease due to defective splicing. Acta Ophthalmol 2018;96:737–743.
8. Tsang SH, Sharma T. Stargardt disease. Adv Exp Med Biol 2018;1085:139–51.
9. Hussain RM, Ciulla TA, Berrocal AM, Gregori NZ, Flynn HW Jr, Lam BL. Stargardt macular dystrophy and evolving therapies. Expert Opin Biol Ther 2018;18:1049–1059.
10. Battu R, Ratra D, Gopal L. Newer therapeutic options for inherited retinal diseases: Gene and cell replacement therapy. Indian J Ophthalmol 2022;70:2316–2325.
11. Strauss RW, Ho A, Muñoz B, Cideciyan AV, Sahel JA, Sunness JS, et al. The natural history of the progression of atrophy secondary to Stargardt Disease (ProgStar) Studies: Design and baseline characteristics: ProgStar report no.1. Ophthalmology 2016;123:817–828.
12. Jin ZB, Gao ML, Deng WL, Wu KC, Sugita S, Mandai M, et al. Stemming retinal regeneration with pluripotent stem cells. Prog Retin Eye Res 2019;69:38–56.
13. Brant Fernandes RA, Lojudice FH, Zago Ribeiro L, Santos da Cruz NF, Polizelli MU, Cristovam PC, et al. Transplantation of subretinal stem cell-derived retinal pigment epithelium for Stargardt disease: A phase I clinical trial. Retina 2023;43:263–274.
14. Li SY, Liu Y, Wang L, Wang F, Zhao TT, Li QY, et al. A phase I clinical trial of human embryonic stem cellderived retinal pigment epithelial cells for early-stage Stargardt macular degeneration: 5-years’ follow-up. Cell Prolif 2021;54:e13100.
15. Weiss JN, Levy S. Stem Cell Ophthalmology Treatment Study (SCOTS): Bone marrow-derived stem cells in the treatment of Stargardt disease. Medicines 2021;8:10.
16. Sung Y, Lee MJ, Choi J, Jung SY, Chong SY, Sung JH, et al. Long-term safety and tolerability of subretinal transplantation of embryonic stem cell-derived retinal pigment epithelium in Asian Stargardt disease patients. Br J Ophthalmol 2021;105:829–837.
17. Cotrim CC, Vieira Messias AM, Jorge R, Siqueira RC. Intravitreal use of a bone marrow mononuclear fraction (BMMF) containing CD34+ cells in patients with Stargardt type macular dystrophy. Stem Cells Int 2020;2020:8828256.
18. Oner A, Gonen ZB, Sevim DG, Smim Kahraman N, Unlu M. Suprachoroidal adipose tissue-derived mesenchymal stem cell implantation in patients with dry-type agerelated macular degeneration and Stargardt’s macular dystrophy: 6-month follow-up results of a phase 2 study. Cell Reprogram 2018;20:329–336.
19. Mehat MS, Sundaram V, Ripamonti C, Robson AG, Smith AJ, Borooah S, et al. Transplantation of human embryonic stem cell-derived retinal pigment epithelial cells in macular degeneration. Ophthalmology 2018;125:1765–1775.
20. Leung EH, Flynn HW Jr, Albini TA, Medina CA. Retinal detachment after subretinal stem cell transplantation. Ophthalmic Surg Lasers Imaging Retina 2016;47:600–601.
21. Schwartz SD, Regillo CD, Lam BL, Eliott D, Rosenfeld PJ, Gregori NZ, 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.
22. Song WK, Park KM, Kim HJ, Lee JH, Choi J, Chong SY, et al. Treatment of macular degeneration using embryonic stem cell-derived retinal pigment epithelium: Preliminary results in Asian patients. Stem Cell Rep 2015;4:860–872.
23. Schwartz SD, Hubschman JP, Heilwell G, FrancoCardenas V, Pan CK, Ostrick RM, et al. Embryonic stem cell trials for macular degeneration: A preliminary report. Lancet 2012;379:713–720.
24. Wert KJ, Skeie JM, Davis RJ, Tsang SH, Mahajan VB. Subretinal injection of gene therapy vectors and stem cells in the perinatal mouse eye. J Vis Exp 2012;69:4286.
25. Lu B, Malcuit C, Wang S, Girman S, Francis P, Lemieux L, et al. Long-term safety and function of RPE from human embryonic stem cells in preclinical models of macular degeneration. Stem Cells 2009;27:2126–2135.
26. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ 2021;372:n71.
27. Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, et al. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. J Clin Epidemiol 2011;64:383–394.
28. Heath Jeffery RC, Chen FK. Stargardt disease: Multimodal imaging: A review. Clin Exp Ophthalmol 2021;49:498–515.
29. Walia S, Fishman GA. Natural history of phenotypic changes in Stargardt macular dystrophy. Ophthalmic Genet 2009;30:63–68.
30. Palejwala NV, Gale MJ, Clark RF, Schlechter C, Weleber RG, Pennesi ME. Insights into autosomal dominant Stargardt-like macular dystrophy through multimodality diagnostic imaging. Retina 2016;36:119–130.
31. Donoso LA, Edwards AO, Frost A, Vrabec T, Stone EM, Hageman GS, et al. Autosomal dominant Stargardt-like macular dystrophy. Surv Ophthalmol 2001;46:149–163.
32. Vasireddy V, Wong P, Ayyagari R. Genetics and molecular pathology of Stargardt-like macular degeneration. Prog Retin Eye Res 2010;29:191–207.
33. Schulz HL, Grassmann F, Kellner U, Spital G, Rüther K, Jägle H, et al. Mutation spectrum of the ABCA4 gene in 335 Stargardt disease patients from a multicenter german cohort-impact of selected deep intronic variants and common SNPs. Invest Ophthalmol Vis Sci 2017;58:394– 403.
34. Tsybovsky Y, Molday RS, Palczewski K. The ATP-binding cassette transporter ABCA4: Structural and functional properties and role in retinal disease. Adv Exp Med Biol 2010;703:105–125.
35. Lu LJ, Liu J, Adelman RA. Novel therapeutics for Stargardt disease. Graefes Arch Clin Exp Ophthalmol 2017;255:1057–1062.
36. Sparrow JR, Boulton M. RPE lipofuscin and its role in retinal pathobiology. Exp Eye Res 2005;80:595–606.
37. Parmar VM, Parmar T, Arai E, Perusek L, Maeda A. A2E-associated cell death and inflammation in retinal pigmented epithelial cells from human induced pluripotent stem cells. Stem Cell Res 2018;27:95–104.
38. Ng ES, Kady N, Hu J, Dave A, Jiang Z, Pei J, et al. Membrane attack complex mediates retinal pigment epithelium cell death in Stargardt macular degeneration. Cells 2022;11:3462.
39. Tanna P, Strauss RW, Fujinami K, Michaelides M. Stargardt disease: Clinical features, molecular genetics, animal models and therapeutic options. Br J Ophthalmol 2017;101:25–30.
40. Chen Y, Okano K, Maeda T, Chauhan V, Golczak M, Maeda A, et al. Mechanism of all-trans-retinal toxicity with implications for Stargardt disease and age-related macular degeneration. J Biol Chem 2012;287:5059–5069.
41. Radu RA, Mata NL, Bagla A, Travis GH. Light exposure stimulates formation of A2E oxiranes in a mouse model of Stargardt’s macular degeneration. Proc Natl Acad Sci USA 2004;101:5928–5933.
42. Teussink MM, Lee MD, Smith RT, van Huet RA, Klaver CC, Klevering BJ, et al. The effect of light deprivation in patients with Stargardt disease. Am J Ophthalmol 2015;159:964–972.e2.
43. Fujinami K, Strauss RW, Chiang JP, Audo IS, Bernstein PS, Birch DG, et al. Detailed genetic characteristics of an international large cohort of patients with Stargardt disease: ProgStar study report 8. Br J Ophthalmol 2019;103:390–397.
44. Lee W, Xie Y, Zernant J, Yuan B, Bearelly S, Tsang SH, et al. Complex inheritance of ABCA4 disease: Four mutations in a family with multiple macular phenotypes. Hum Genet 2016;135:9–19.
45. Arrigo A, Grazioli A, Romano F, Aragona E, Bordato A, di Nunzio C, et al. Choroidal patterns in Stargardt disease: Correlations with visual acuity and disease progression. J Clin Med 2019;8:1388.
46. Collison FT, Fishman GA. Visual acuity in patients with Stargardt disease after age 40. Retina 2018;38:2387– 2394.
47. Fujinami K, Zernant J, Chana RK, Wright GA, Tsunoda K, Ozawa Y, et al. ABCA4 gene screening by next-generation sequencing in a British cohort. Invest Ophthalmol Vis Sci 2013;54:6662–6674.
48. Lambertus S, van Huet RA, Bax NM, Hoefsloot LH, Cremers FP, Boon CJ, et al. Early-onset Stargardt disease: Phenotypic and genotypic characteristics. Ophthalmology 2015;122:335–344.
49. Fujinami K, Zernant J, Chana RK, Wright GA, Tsunoda K, Ozawa Y, et al. Clinical and molecular characteristics of childhood-onset Stargardt disease. Ophthalmology 2015;122:326–334.
50. Ramsden CM, Powner MB, Carr AJ, Smart MJ, da Cruz L, Coffey PJ. Stem cells in retinal regeneration: Past, present and future. Development 2013;140:2576–2585.
51. Araki R, Uda M, Hoki Y, Sunayama M, Nakamura M, Ando S, et al. Negligible immunogenicity of terminally differentiated cells derived from induced pluripotent or embryonic stem cells. Nature 2013;494:100–104.
52. Mead B, Berry M, Logan A, Scott RA, Leadbeater W, Scheven BA. Stem cell treatment of degenerative eye disease. Stem Cell Res 2015;14:243–257.
53. 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.
54. Ahmed I, Johnston RJ Jr, Singh MS. Pluripotent stem cell therapy for retinal diseases. Ann Transl Med 2021;9:1279.
55. Maeda A, Mandai M, Takahashi M. Gene and induced pluripotent stem cell therapy for retinal diseases. Annu Rev Genomics Hum Genet 2019;20:201–216.
56. Han F, Xu G. Stem cell transplantation therapy for retinal degenerative diseases. Adv Exp Med Biol 2020;1266:127– 139.
57. Sharma A, Jaganathan BG. Stem cell therapy for retinal degeneration: The evidence to date. Biologics 2021;15:299–306.
58. Ding DC, Shyu WC, Lin SZ. Mesenchymal stem cells. Cell Transplant 2011;20:5–14.
59. Fu X, Liu G, Halim A, Ju Y, Luo Q, Song AG. Mesenchymal stem cell migration and tissue repair. Cells 2019;8:784.
60. Lin Y, Ren X, Chen Y, Chen D. Interaction between mesenchymal stem cells and retinal degenerative microenvironment. Front Neurosci 2021;14:617377.
61. Xian B, Huang B. The immune response of stem cells in subretinal transplantation. Stem Cell Res Ther 2015;6:161.
62. Streilein JW, Ma N, Wenkel H, Ng TF, Zamiri P. Immunobiology and privilege of neuronal retina and pigment epithelium transplants. Vision Res 2002;42:487– 495.
63. Sugita S, Horie S, Nakamura O, Maruyama K, Takase H, Usui Y. Acquisition of T regulatory function in cathepsin L-inhibited T cells by eye-derived CTLA-2alpha during inflammatory conditions. J Immunol 2009;183:5013–5022.
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