Future Directions

  • Mandeep S. Singh
  • Marco A. Zarbin
Part of the Stem Cell Biology and Regenerative Medicine book series (STEMCELL)


Several phase 1/2 clinical trials have focused on investigating the safety and feasibility of retinal cell therapy in diseases such as age-related macular degeneration, retinitis pigmentosa, and Stargardt disease. Technical improvements are anticipated in areas such as surgical delivery methods, composite cellular patches, and synthetic basement substrates for optimal retinal protection and regeneration. Immunosuppression protocols are being optimized in order to avoid the side effects of long-term systemic immunosuppression. The development of appropriate clinical trial endpoints will facilitate assessment of the efficacy of retinal stem cell therapy in phase 3 clinical trials. Greater regulatory oversight and public education are needed to eliminate the dangers associated with direct-to-consumer cell therapy, so that the progress of properly designed and supervised clinical trials is not impeded.


Cell therapy Clinical trials Age-related macular degeneration Retinitis pigmentosa Stargardt disease Immunosuppression Surgical delivery Regulatory oversight 


  1. 1.
    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.CrossRefGoogle Scholar
  2. 2.
    Park SS, Bauer G, Abedi M, et al. Intravitreal autologous bone marrow CD34+ cell therapy for ischemic and degenerative retinal disorders: preliminary phase 1 clinical trial findings. Invest Ophthalmol Vis Sci. 2014;56(1):81–9.CrossRefGoogle Scholar
  3. 3.
    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.CrossRefGoogle Scholar
  4. 4.
    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.CrossRefGoogle Scholar
  5. 5.
    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):eaao4097.CrossRefGoogle Scholar
  6. 6.
    Ho AC, Chang TS, Samuel M, Williamson P, Willenbucher RF, Malone T. Experience with a subretinal cell-based therapy in patients with geographic atrophy secondary to age-related macular degeneration. Am J Ophthalmol. 2017;179:67–80.CrossRefGoogle Scholar
  7. 7.
    Singh MS, MacLaren RE. Stem cell treatment for age-related macular degeneration: the challenges. Invest Ophthalmol Vis Sci. 2018;59(4):Amd78–amd82.CrossRefGoogle Scholar
  8. 8.
    Sugino IK, Gullapalli VK, Sun Q, et al. Cell-deposited matrix improves retinal pigment epithelium survival on aged submacular human Bruch’s membrane. Invest Ophthalmol Vis Sci. 2011;52(3):1345–58.CrossRefGoogle Scholar
  9. 9.
    Sugino IK, Sun Q, Cheewatrakoolpong N, Malcuit C, Zarbin MA. Biochemical restoration of aged human Bruch's membrane: experimental studies to improve retinal pigment epithelium transplant survival and differentiation. Dev Ophthalmol. 2014;53:133–42.CrossRefGoogle Scholar
  10. 10.
    Lambertus S, Bax NM, Fakin A, et al. Highly sensitive measurements of disease progression in rare disorders: developing and validating a multimodal model of retinal degeneration in Stargardt disease. PLoS One. 2017;12(3):e0174020.CrossRefGoogle Scholar
  11. 11.
    Berson EL, Sandberg MA, Rosner B, Birch DG, Hanson AH. Natural course of retinitis pigmentosa over a three-year interval. Am J Ophthalmol. 1985;99(3):240–51.CrossRefGoogle Scholar
  12. 12.
    Endo T, Fujikado T, Hirota M, Kanda H, Morimoto T, Nishida K. Light localization with low-contrast targets in a patient implanted with a suprachoroidal–transretinal stimulation retinal prosthesis. Graefes Arch Clin Exp Ophthalmol. 2018;256(9):1723–9.CrossRefGoogle Scholar
  13. 13.
    Russell S, Bennett J, Wellman JA, 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. 2017;390(10097):849–60.CrossRefGoogle Scholar
  14. 14.
    Hariri AH, Velaga SB, Girach A, et al. Measurement and reproducibility of preserved ellipsoid zone area and preserved retinal pigment epithelium area in eyes with choroideremia. Am J Ophthalmol. 2017;179:110–7.CrossRefGoogle Scholar
  15. 15.
    Hariri AH, Zhang HY, Ho A, et al. Quantification of ellipsoid zone changes in retinitis pigmentosa using en face spectral domain-optical coherence tomography. JAMA Ophthalmol. 2016;134(6):628–35.CrossRefGoogle Scholar
  16. 16.
    Smith TB, Parker M, Steinkamp PN, Weleber RG, Smith N, Wilson DJ. Structure-function modeling of optical coherence tomography and standard automated perimetry in the retina of patients with autosomal dominant retinitis pigmentosa. PLoS One. 2016;11(2):e0148022.CrossRefGoogle Scholar
  17. 17.
    Liang J, Williams DR, Miller DT. Supernormal vision and high-resolution retinal imaging through adaptive optics. J Opt Soc Am A Opt Image Sci Vis. 1997;14(11):2884–92.CrossRefGoogle Scholar
  18. 18.
    Roorda A, Williams DR. The arrangement of the three cone classes in the living human eye. Nature. 1999;397(6719):520–2.CrossRefGoogle Scholar
  19. 19.
    Foote KG, Loumou P, Griffin S, et al. Relationship between foveal cone structure and visual acuity measured with adaptive optics scanning laser ophthalmoscopy in retinal degeneration. Invest Ophthalmol Vis Sci. 2018;59(8):3385–93.CrossRefGoogle Scholar
  20. 20.
    Prow T, Grebe R, Merges C, et al. Nanoparticle tethered antioxidant response element as a biosensor for oxygen induced toxicity in retinal endothelial cells. Mol Vis. 2006;12:616–25.PubMedGoogle Scholar
  21. 21.
    Prow TW, Bhutto I, Grebe R, et al. Nanoparticle-delivered biosensor for reactive oxygen species in diabetes. Vision Res. 2008;48(3):478–85.CrossRefGoogle Scholar
  22. 22.
    Kuriyan AE, Albini TA, Townsend JH, et al. Vision loss after intravitreal injection of autologous “stem cells” for AMD. N Engl J Med. 2017;376(11):1047–53.CrossRefGoogle Scholar
  23. 23.
    Saraf SS, Cunningham MA, Kuriyan AE, et al. Bilateral retinal detachments after intravitreal injection of adipose-derived ‘stem cells’ in a patient with exudative macular degeneration. Ophthalmic Surg Lasers Imaging Retina. 2017;48(9):772–5.CrossRefGoogle Scholar
  24. 24.
    The Food and Drug Administration. FDA warns about US stem cell therapies. 2017.
  25. 25.
    The Food and Drug Administration. FDA seeks permanent injunctions against two stem cell clinics. 2018. Accessed 15 May 2018.
  26. 26.
    Turner L, Knoepfler P. Selling stem cells in the USA: assessing the direct-to-consumer industry. Cell Stem Cell. 2016;19(2):154–7.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Mandeep S. Singh
    • 1
  • Marco A. Zarbin
    • 2
  1. 1.Wilmer Eye Institute, Johns Hopkins University School of MedicineBaltimoreUSA
  2. 2.Institute of Ophthalmology and Visual Science, Rutgers New Jersey Medical SchoolNewarkUSA

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