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Regenerative and restorative medicine for eye disease

An Author Correction to this article was published on 09 August 2022

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Abstract

Causes of blindness differ across the globe; in higher-income countries, most blindness results from the degeneration of specific classes of cells in the retina, including retinal pigment epithelium (RPE), photoreceptors, and retinal ganglion cells. Advances over the past decade in retinal regenerative medicine have allowed each of these cell types to be produced ex vivo from progenitor stem cells. Here, we review progress in applying these technologies to cell replacement — with the goal of vision restoration in degenerative disease. We discuss the landscape of human clinical trials for RPE transplantation and advanced preclinical studies for other cell types. We also review progress toward in situ repair of retinal degeneration using endogenous progenitor cells. Finally, we provide a high-level overview of progress toward prosthetic ocular vision restoration, including advanced photovoltaic devices, opsin-based gene therapy, and small-molecule photoswitches. Progress in each of these domains is at or near the human clinical-trial stage, bringing the audacious goal of vision restoration within sight.

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Fig. 1: Visual pathways and approaches to vision restoration.
Fig. 2: Cell sources for replacement therapies.

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References

  1. GBD 2019 Blindness and Vision Impairment Collaborators. Trends in prevalence of blindness and distance and near vision impairment over 30 years: an analysis for the Global Burden of Disease Study. Lancet Glob. Health 9, e130–e143 (2021).

  2. Rein, D. B. et al. The economic burden of vision loss and blindness in the United States. Ophthalmology 129, 369–378 (2021).

  3. Age-Related Eye Disease Study Research et al. The relationship of dietary carotenoid and vitamin A, E, and C intake with age-related macular degeneration in a case-control study: AREDS Report No. 22. Arch. Ophthalmol. 125, 1225–1232 (2007).

    Article  Google Scholar 

  4. Caras, I. W., Collins, L. R. & Creasey, A. A. A stem cell journey in ophthalmology: from the bench to the clinic. Stem Cells Transl. Med. 10, 1581–1587 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Haruta, M. et al. In vitro and in vivo characterization of pigment epithelial cells differentiated from primate embryonic stem cells. Invest. Ophthalmol. Vis. Sci. 45, 1020–1025 (2004).

    Article  PubMed  Google Scholar 

  6. Idelson, M. et al. Directed differentiation of human embryonic stem cells into functional retinal pigment epithelium cells. Cell Stem Cell 5, 396–408 (2009).

    Article  CAS  PubMed  Google Scholar 

  7. Osakada, F., Ikeda, H., Sasai, Y. & Takahashi, M. Stepwise differentiation of pluripotent stem cells into retinal cells. Nat. Protoc. 4, 811–824 (2009).

    Article  CAS  PubMed  Google Scholar 

  8. Luo, J. et al. Human retinal progenitor cell transplantation preserves vision. J. Biol. Chem. 289, 6362–6371 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Carr, A. J. et al. Protective effects of human iPS-derived retinal pigment epithelium cell transplantation in the retinal dystrophic rat. PLoS ONE 4, e8152 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Schwartz, S. D. 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 385, 509–516 (2015).

    Article  PubMed  Google Scholar 

  11. Mehat, M. S. et al. Transplantation of human embryonic stem cell-derived retinal pigment epithelial cells in macular degeneration. Ophthalmology 125, 1765–1775 (2018).

    Article  PubMed  Google Scholar 

  12. Sharma, R. et al. Clinical-grade stem cell-derived retinal pigment epithelium patch rescues retinal degeneration in rodents and pigs. Sci. Transl. Med. 11, eaaw7624 (2019).

    Article  Google Scholar 

  13. Chirco, K. R. et al. Preparation and evaluation of human choroid extracellular matrix scaffolds for the study of cell replacement strategies. Acta Biomater. 57, 293–303 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Koss, M. J. et al. Subretinal implantation of a monolayer of human embryonic stem cell-derived retinal pigment epithelium: a feasibility and safety study in Yucatan minipigs. Graefes Arch. Clin. Exp. Ophthalmol. 254, 1553–1565 (2016).

    Article  CAS  PubMed  Google Scholar 

  15. Kashani, A. H. et al. One-year follow-up in a phase 1/2a clinical trial of an allogeneic RPE cell bioengineered implant for advanced dry age-related macular degeneration. Transl. Vis. Sci. Technol. 10, 13 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Lingam, S. et al. cGMP-grade human iPSC-derived retinal photoreceptor precursor cells rescue cone photoreceptor damage in non-human primates. Stem Cell Res. Ther. 12, 464 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Shirai, H. et al. Transplantation of human embryonic stem cell-derived retinal tissue in two primate models of retinal degeneration. Proc. Natl Acad. Sci. USA 113, E81–E90 (2016).

    Article  CAS  PubMed  Google Scholar 

  18. Chao, J. R. et al. Transplantation of human embryonic stem cell-derived retinal cells into the subretinal space of a non-human primate. Transl. Vis. Sci. Technol. 6, 4 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Kupperman, B. D. et al. ARVO annual meeting abstract: Safety and activity of a single, intravitreal injection of human retinal progenitor cells (JCell) for treatment of retinitis pigmentosa (RP). Invest Ophthal Vis Sci. 59, 2987 (2018).

  20. Lin, B., McLelland, B. T., Mathur, A., Aramant, R. B. & Seiler, M. J. Sheets of human retinal progenitor transplants improve vision in rats with severe retinal degeneration. Exp. Eye Res. 174, 13–28 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Nakano, T. et al. Self-formation of optic cups and storable stratified neural retina from human ESCs. Cell Stem Cell 10, 771–785 (2012).

    Article  CAS  PubMed  Google Scholar 

  22. Capowski, E. E. et al. Reproducibility and staging of 3D human retinal organoids across multiple pluripotent stem cell lines. Development 146, dev171686 (2019).

    PubMed  PubMed Central  Google Scholar 

  23. Zhong, X. et al. Generation of three-dimensional retinal tissue with functional photoreceptors from human iPSCs. Nat. Commun. 5, 4047 (2014).

    Article  CAS  PubMed  Google Scholar 

  24. Ribeiro, J. et al. Restoration of visual function in advanced disease after transplantation of purified human pluripotent stem cell-derived cone photoreceptors. Cell Rep. 35, 109022 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Aboualizadeh, E. et al. Imaging transplanted photoreceptors in living nonhuman primates with single-cell resolution. Stem Cell Rep. 15, 482–497 (2020).

    Article  CAS  Google Scholar 

  26. Morgan, J. & Wong, R. Development of cell types and synaptic connections in the retina. in Webvision: The Organization of the Retina and Visual System (eds. Kolb, H., Fernandez, E. & Nelson, R.) (University of Utah Health Sciences, 1995).

  27. Marc, R. E., Jones, B. W., Watt, C. B. & Strettoi, E. Neural remodeling in retinal degeneration. Prog. Retin. Eye Res. 22, 607–655 (2003).

    Article  PubMed  Google Scholar 

  28. Sekirnjak, C. et al. Changes in physiological properties of rat ganglion cells during retinal degeneration. J. Neurophysiol. 105, 2560–2571 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Shekhar, K. et al. Comprehensive classification of retinal bipolar neurons by single-cell transcriptomics. Cell 166, 1308–1323.e1330 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Gabriel, E. et al. Human brain organoids assemble functionally integrated bilateral optic vesicles. Cell Stem Cell 28, 1740–1757 e1748 (2021).

    Article  CAS  PubMed  Google Scholar 

  31. Miltner, A. M. & La Torre, A. Retinal ganglion cell replacement: current status and challenges ahead. Dev. Dyn. 248, 118–128 (2019).

    Article  PubMed  Google Scholar 

  32. Xiao, D. et al. In vivo regeneration of ganglion cells for vision restoration in mammalian retinas. Front. Cell Dev. Biol. 9, 755544 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Peng, Y. R. et al. Molecular classification and comparative taxonomics of foveal and peripheral cells in primate retina. Cell 176, 1222–1237 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Venugopalan, P. et al. Transplanted neurons integrate into adult retinas and respond to light. Nat. Commun. 7, 10472 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wu, Y. R. et al. Transplanted mouse embryonic stem cell-derived retinal ganglion cells integrate and form synapses in a retinal ganglion cell-depleted mouse model. Invest. Ophthalmol. Vis. Sci. 62, 26 (2021).

    PubMed  PubMed Central  Google Scholar 

  36. Lahne, M., Nagashima, M., Hyde, D. R. & Hitchcock, P. F. Reprogramming Müller glia to regenerate retinal neurons. Annu Rev. Vis. Sci. 6, 171–193 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Dyer, M. A. & Cepko, C. L. Control of Muller glial cell proliferation and activation following retinal injury. Nat. Neurosci. 3, 873–880 (2000).

    Article  CAS  PubMed  Google Scholar 

  38. Hoang, T. et al. Gene regulatory networks controlling vertebrate retinal regeneration. Science 370, eabb8598 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Jorstad, N. L. et al. Stimulation of functional neuronal regeneration from Müller glia in adult mice. Nature 548, 103–107 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Livesey, F. J. & Cepko, C. L. Vertebrate neural cell-fate determination: lessons from the retina. Nat. Rev. Neurosci. 2, 109–118 (2001).

    Article  CAS  PubMed  Google Scholar 

  41. Jorstad, N. L. et al. Stimulation of functional neuronal regeneration from Muller glia in adult mice. Nature 548, 103–107 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Todd, L. et al. Efficient stimulation of retinal regeneration from Muller glia in adult mice using combinations of proneural bHLH transcription factors. Cell Rep. 37, 109857 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Scholler, J. et al. Dynamic full-field optical coherence tomography: 3D live-imaging of retinal organoids. Light Sci. Appl. 9, 140 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Rossi, E. A. et al. Imaging individual neurons in the retinal ganglion cell layer of the living eye. Proc. Natl Acad. Sci. USA 114, 586–591 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Liu, Z. et al. Quantification of retinal ganglion cell morphology in human glaucomatous eyes. Invest. Ophthalmol. Vis. Sci. 62, 34 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Palczewska, G. et al. Two-photon imaging of the mammalian retina with ultrafast pulsing laser. JCI Insight 3, e121555 (2018).

    Article  PubMed Central  Google Scholar 

  47. Pandiyan, V. P. et al. The optoretinogram reveals the primary steps of phototransduction in the living human eye. Sci. Adv. 6, eabc1124 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Ahuja, A. K. et al. Blind subjects implanted with the Argus II retinal prosthesis are able to improve performance in a spatial-motor task. Br. J. Ophthalmol. 95, 539–543 (2011).

    Article  CAS  PubMed  Google Scholar 

  49. Dagnelie, G. et al. Performance of real-world functional vision tasks by blind subjects improves after implantation with the Argus(R) II retinal prosthesis system. Clin. Exp. Ophthalmol. 45, 152–159 (2017).

    Article  PubMed  Google Scholar 

  50. Nanduri, D. et al. Frequency and amplitude modulation have different effects on the percepts elicited by retinal stimulation. Invest. Ophthalmol. Vis. Sci. 53, 205–214 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Stingl, K. et al. Interim results of a multicenter trial with the new electronic subretinal implant alpha AMS in 15 patients blind from inherited retinal degenerations. Front. Neurosci. 11, 445 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Ayton, L. N. et al. An update on retinal prostheses. Clin. Neurophysiol. 131, 1383–1398 (2020).

    Article  PubMed  Google Scholar 

  53. Lorach, H. et al. Photovoltaic restoration of sight with high visual acuity. Nat. Med. 21, 476–482 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Palanker, D., Le Mer, Y., Mohand-Said, S., Muqit, M. & Sahel, J. A. Photovoltaic restoration of central vision in atrophic age-related macular degeneration. Ophthalmology 127, 1097–1104 (2020).

    Article  PubMed  Google Scholar 

  55. Maguire, A. M. et al. Efficacy, safety, and durability of voretigene neparvovec-rzyl in RPE65 mutation-associated inherited retinal dystrophy: results of phase 1 and 3 trials. Ophthalmology 126, 1273–1285 (2019).

    Article  PubMed  Google Scholar 

  56. Russell, S. et al. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet 390, 849–860 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Cideciyan, A. V. et al. Human retinal gene therapy for Leber congenital amaurosis shows advancing retinal degeneration despite enduring visual improvement. Proc. Natl Acad. Sci. USA 110, E517–E525 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Bucher, K., Rodriguez-Bocanegra, E., Dauletbekov, D. & Fischer, M. D. Immune responses to retinal gene therapy using adeno-associated viral vectors — implications for treatment success and safety. Prog. Retin. Eye Res. 83, 100915 (2021).

    Article  CAS  PubMed  Google Scholar 

  59. Van Gelder, R. N. Gene therapy approaches to slow or reverse blindness from inherited retinal degeneration: growth factors and optogenetics. Int. Ophthalmol. Clin. 61, 209–228 (2021).

    Article  PubMed  Google Scholar 

  60. Kauper, K. et al. Two-year intraocular delivery of ciliary neurotrophic factor by encapsulated cell technology implants in patients with chronic retinal degenerative diseases. Invest. Ophthalmol. Vis. Sci. 53, 7484–7491 (2012).

    Article  CAS  PubMed  Google Scholar 

  61. Chew, E. Y. et al. Effect of ciliary neurotrophic factor on retinal neurodegeneration in patients with macular telangiectasia type 2: a randomized clinical trial. Ophthalmology 126, 540–549 (2019).

    Article  PubMed  Google Scholar 

  62. Sahel, J. A. et al. Partial recovery of visual function in a blind patient after optogenetic therapy. Nat. Med. 27, 1223–1229 (2021).

    Article  CAS  PubMed  Google Scholar 

  63. Berry, M. H. et al. Restoration of high-sensitivity and adapting vision with a cone opsin. Nat. Commun. 10, 1221 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Polosukhina, A. et al. Photochemical restoration of visual responses in blind mice. Neuron 75, 271–282 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Tochitsky, I. et al. Restoring visual function to blind mice with a photoswitch that exploits electrophysiological remodeling of retinal ganglion cells. Neuron 81, 800–813 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Tochitsky, I. et al. How azobenzene photoswitches restore visual responses to the blind retina. Neuron 92, 100–113 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Koga, K., Wang, B. & Kaneko, S. Current and furutre perspectives of HLA-edited induced pluripotent stem cells. Inflamm. Regen. 40, 223 (2020).

    Article  Google Scholar 

  68. Liu, Y. & Lee, R. K. Cell transplantation to replace retinal ganglion cells faces challenges — the Switchboard Dilemma. Neural Regen. Res 16, 1138–1143 (2021).

    Article  PubMed  Google Scholar 

  69. Fligor, C. M. et al. Extension of retinofugal projections in an assembled model of human pluripotent stem cell-derived organoids. Stem Cell Rep. 16, 2228–2241 (2021).

    Article  CAS  Google Scholar 

  70. Yungher, B. J., Ribeiro, M. & Park, K. K. Regenerative responses and axon pathfinding of retinal ganglion cells in chronically injured mice. Invest. Ophthalmol. Vis. Sci. 58, 1743–1750 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. De Lima, S., Koriyama, Y., Kurimoto, T. & Benowitz, L. Full-length axon regeneration in the adult mouse optic nerve and partial recovery of simple visual behaviors. Proc. Natl Acad. Sci. USA 109, 9149–9154 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Glennon, E., Svirsky, M. A. & Froemke, R. C. Auditory cortical plasticity in cochlear implant users. Curr. Opin. Neurobiol. 60, 108–114 (2020).

    Article  CAS  PubMed  Google Scholar 

  73. Palanker, D., Le Mer, Y., Mohand-Said, S. & Sahel, J. A. Simultaneous perception of prosthetic and natural vision in AMD patients. Nat. Commun. 13, 513 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Schwartz, S. D. et al. Embryonic stem cell trials for macular degeneration: a preliminary report. Lancet 379, 713–720 (2012).

    Article  CAS  PubMed  Google Scholar 

  75. Petoe, M. A. et al. A second-generation (44-channel) suprachoroidal retinal prosthesis: interim clinical trial results. Transl. Vis. Sci. Technol. 10, 12 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  76. Morgan, J. L., Dhingra, A., Vardi, N. & Wong, R. O. L. Axons and dendrites originate from neuroepithelial-like processes of retinal bipolar neurons. Nat. Neurosci. 9, 85–92 (2006).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Special thanks to P. Sieving for conceptualizing the Audacious Goals Initiative and pushing the field of regenerative medicine in the eye forward. Thanks also to S. Becker for shepherding the vision of AGI and its progress. R.N.V.G. acknowledges support of an unrestricted grant from Research to Prevent Blindness and the Mark Daly, MD Research Fund.

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Correspondence to Russell N. Van Gelder.

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R.N.V.G., R.O.W., M.F.C., C.N.S., M.A.D. and T.N.G. have no competing interests. L.A.L. serves as paid consultant to Pirlenia, Janssen, Roche, Neuoptika, Quark, Perfuse, Genentech, Regenera, Unity, Eyevensys, Santen and Aerie.

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Nature Medicine thanks Daniel Palanker and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary handling editor: Karen O’Leary, in collaboration with the Nature Medicine team.

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Van Gelder, R.N., Chiang, M.F., Dyer, M.A. et al. Regenerative and restorative medicine for eye disease. Nat Med 28, 1149–1156 (2022). https://doi.org/10.1038/s41591-022-01862-8

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