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Cell Therapy pp 249-279 | Cite as

Cell Therapy for Ophthalmic Diseases

  • Konrad KauperEmail author
  • Arne Nystuen
Chapter
Part of the Molecular and Translational Medicine book series (MOLEMED)

Abstract

Over the past several decades, cell-based strategies for retinal disease treatment have been an area of increasing research in both the basic and translational sciences. The motivation for this increased effort is the lack of treatment options for patients with debilitating and permanent loss of vision. The intricate anatomy and complex physiology of the eye pose unique challenges for potential ophthalmic therapeutics. These challenges are exacerbated when the treatment requires efficient delivery of the therapeutic to the posterior eye or attempts to regenerate areas of diseased retina. In these situations cell-based therapies may provide the answer. Until recently the technical and regulatory challenges and appropriate concerns for patient safety and efficacy presented unique hurdles to the advancement of cell-based technologies for treatment of eye diseases. However, improvements in genetic engineering, recombinant protein production, stem cell technology, and cell therapy manufacturing have been developed which are overcoming many of the challenges encountered in early attempts to develop effective and safe ophthalmic cell therapy products. As a result of these technical advances, supported by accumulating safety data and the suggestion of beneficial treatment outcomes from recent clinical trials, a real possibility exists that cell-based therapies may soon become common treatment options for a wide range of ophthalmic disorders.

Keywords

Macular degeneration Geographic atrophy Retinitis pigmentosa Macular telangiectasia Inner/outer segment (IS/OS) Retinal pigment epithelium Ellipsoid zone (EZ) Fovea Photoreceptor Cone cell Rod cell Ganglion cell Müller cell Encapsulated cell technology (ECT) Idiopathic macular telangiectasia type 2 (MacTel) Adeno-associated virus (AAV) RPE65 Induced pluripotent stem cell (iPSC) Optical coherence tomography (OCT) En face Neuroprotection Cytokines Ciliary neurotrophic factor (CNTF) Vascular endothelial growth factor receptor (VEGFR) 

References

  1. 1.
    Statistics on vision impairment: a resource manual. 5th ed. 2002 [Internet]. http://gesta.org/estudos/statistics0402.pdf
  2. 2.
    Prevention of blindness and visual impairment. World Health Organization. 2016. http://www.who.int/blindness/causes/en/
  3. 3.
    National Center for Health Statistics. Summary health statistics for U.S. adults: national health interview survey. 2012. http://www.cdc.gov/nchs/data/series/sr_10/sr10_260.pdf
  4. 4.
    The economic burden of vision loss and eye disorders in the United States. Prevent blindness America. http://costofvision.preventblindness.org/costs/
  5. 5.
    Purves D, Augustine GJ, Fitzpatrick D, Katz LC, Lamantia A-S, McNamara JO, et al., editors. Neuroscience. 2nd ed. Sunderland, MA: Sinauer Associates; 2001.Google Scholar
  6. 6.
    Marmor MF. Structure function and disease of the retinal pigment epithelium. In: Marmor MF, Wolfensberger TJ, editors. The retinal pigment epithelium. New York: Oxford University Press; 1998.Google Scholar
  7. 7.
    Gardner TW, Antonetti DA, Barber AJ, Lieth E, Tarbell JA. The molecular structure and function of the inner blood–retinal barrier. Doc Ophthalmol. 1999;97:229–37.PubMedCrossRefGoogle Scholar
  8. 8.
    Kolb H, Fernandez E, Nelson R. Webvision. The organization of the retina and visual system [Internet]. Salt Lake City, UT: University of Utah Health Sciences Center; 1995. http://www.ncbi.nlm.nih.gov/pubmed/21413389 Google Scholar
  9. 9.
    Daiger S. RetNet: summaries of genes and loci causing retinal diseases. Houston, TX: The University of Texas Health Science Center; 1996–2016. http://sph.uth.edu/retnet/
  10. 10.
    Kaiser PK, Brown DM, Zhang K, et al. Ranibizumab for predominantly classic neovascular age-related macular degeneration: subgroup analysis of first-year ANCHOR results. Am J Ophthalmol. 2007;144(6):850–7.PubMedCrossRefGoogle Scholar
  11. 11.
    Heier JS, Brown DM, Chong V, et al. VIEW 1 and VIEW 2 Study Groups. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology. 2012;119(12):2537–48. doi: 10.1016/j.ophtha.2012.09.006.
  12. 12.
    Klein R, Blodi BA, Meuer SM, Myers CE, Chew EY, Klein BE. The prevalence of macular telangiectasia type 2 in the Beaver Dam eye study. Am J Ophthalmol. 2010;150(1):55–62.e2.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Sallo FB, Peto T, Egan C, Wolf-Schnurrbusch UE, Clemons TE, Gillies MC, Pauleikhoff D, Rubin GS, Chew EY, Bird AC, MacTel Study Group. The IS/OS junction layer in the natural history of type 2 idiopathic macular telangiectasia. Invest Ophthalmol Vis Sci. 2012;53(12):7889–95.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Powner MB, Gillies MC, Tretiach M, Scott A, Guymer RH, Hageman GS, Fruttiger M. Perifoveal Müller cell depletion in a case of macular telangiectasia type 2. Ophthalmology. 2010;117(12):2407–16.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Jacob J, Krivosic V, Paques M, Tadayoni R, Gaudric A. Cone density loss on adaptive optics in early macular telangiectasia type 2. Retina. 2016;36(3):545–51.PubMedCrossRefGoogle Scholar
  16. 16.
    Kass MA, Heuer DK, Higginbotham EJ, et al. The ocular hypertension treatment study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120(6):701–13.PubMedCrossRefGoogle Scholar
  17. 17.
    Anderson DR. Normal tension glaucoma study collaborative normal tension glaucoma study. Curr Opin Ophthalmol. 2003;14(2):86–90.PubMedCrossRefGoogle Scholar
  18. 18.
    Drance SM. The collaborative normal-tension glaucoma study and some of its lessons. Can J Ophthalmol. 1999;34(1):1–6.PubMedGoogle Scholar
  19. 19.
    Urtti A. Challenges and obstacles of ocular pharmacokinetics and drug delivery. Adv Drug Deliv Rev. 2006;58(11):1131–5.PubMedCrossRefGoogle Scholar
  20. 20.
    Prausnitz MR, Noonan JS. Permeability of cornea, sclera, and conjunctiva: a literature analysis for drug delivery to the eye. J Pharm Sci. 1998;87(12):1479–88.PubMedCrossRefGoogle Scholar
  21. 21.
    Del Amo EM, Urtti A. Current and future ophthalmic drug delivery systems. A shift to the posterior segment. Drug Discov Today. 2008;13(3–4):135–43.PubMedGoogle Scholar
  22. 22.
    Jiang LQ, Jorquera M, Streilein JW. Subretinal space and vitreous cavity as immunologically privileged sites for retinal allografts. Invest Ophthalmol Vis Sci. 1993;34(12):3347–54.PubMedGoogle Scholar
  23. 23.
    Kaplan HJ, Streilein JW. Immune response to immunization via the anterior chamber of the eye. I. F. Lymphocyte-induced immune deviation. J Immunol. 1977;118(3):809–14.PubMedGoogle Scholar
  24. 24.
    Grisanti S, Ishioka M, Kosiewicz M, Jiang LQ. Immunity and immune privilege elicited by cultured retinal pigment epithelial cell transplants. Invest Ophthalmol Vis Sci. 1997;38(8):1619–26.PubMedGoogle Scholar
  25. 25.
    Dana MR, Dai R, Zhu S, Yamada J, Streilein JW. Interleukin-1 receptor antagonist suppresses Langerhans cell activity and promotes ocular immune privilege. Invest Ophthalmol Vis Sci. 1998;39(1):70–7.PubMedGoogle Scholar
  26. 26.
    Niederkorn JY. Mechanisms of immune privilege in the eye and hair follicle. J Investig Dermatol Symp Proc. 2003;8(2):168–72.PubMedCrossRefGoogle Scholar
  27. 27.
    Taylor AW. Ocular immune privilege and transplantation. Front Immunol. 2016;7:37.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Leader B, Baca QJ, Golan DE. Protein therapeutics: a summary and pharmacological classification. Nat Rev Drug Discov. 2008;7(1):21–39.PubMedCrossRefGoogle Scholar
  29. 29.
    Rich RM, Rosenfeld PJ, Puliafito CA, et al. Short-term safety and efficacy of intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Retina. 2006;26:495–511.PubMedCrossRefGoogle Scholar
  30. 30.
    Ferrara N, Damico L, Shams N, Lowman H, Kim R. Development of ranibizumab, an anti-vascular endothelial growth factor antigen binding fragment, as therapy for neovascular age-related macular degeneration. Retina. 2006;26(8):859–70.PubMedCrossRefGoogle Scholar
  31. 31.
    Ferrara N, Hillan KJ, Gerber HP, Novotny W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov. 2004;3(5):391–400.PubMedCrossRefGoogle Scholar
  32. 32.
    Peterson N. Advances in monoclonal antibody technology: genetic engineering of mice, cells, and immunoglobulins. ILAR J. 2005;46(3):314–9. doi: 10.1093/ilar.46.3.314.PubMedCrossRefGoogle Scholar
  33. 33.
    Holash J, Davis S, Papadopoulos N, et al. VEGF-trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci U S A. 2002;99(17):11393–8.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Haines JL, Hauser MA, Schmidt S, et al. Complement factor H variant increases the risk of age-related macular degeneration. Science. 2005;308(5720):419–21.PubMedCrossRefGoogle Scholar
  35. 35.
    Edwards AO, Ritter R 3rd, Abel KJ, Manning A, Panhuysen C, Farrer LA. Complement factor H polymorphism and age-related macular degeneration. Science. 2005;308(5720):421–4.PubMedCrossRefGoogle Scholar
  36. 36.
    Stanton CM, Yates JR, den Hollander AI, et al. Complement factor D in age-related macular degeneration. Invest Ophthalmol Vis Sci. 2011;52(12):8828–34.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Jack LS, Sadiq MA, Do DV, Nguyen QD. Emixustat and lampalizumab: potential therapeutic options for geographic atrophy. Dev Ophthalmol. 2016;55:302–9.PubMedCrossRefGoogle Scholar
  38. 38.
    LaVail MM, Unoki K, Yasumura D, Matthes MT, Yancopoulos GD, Steinberg RH. Multiple growth factors, cytokines, and neurotrophins rescue photoreceptors from the damaging effects of constant light. Proc Natl Acad Sci U S A. 1992;89(23):11249–53.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Cui Q, So KF, Yip HK. Major biological effects of neurotrophic factors on retinal ganglion cells in mammals. Biol Signals Recept. 1998;7(4):220–6.PubMedCrossRefGoogle Scholar
  40. 40.
    LaVail MM, Yasumura D, Matthes MT, Lau-Villacorta C, Unoki K, Sung CH, Steinberg RH. Protection of mouse photoreceptors by survival factors in retinal degenerations. Invest Ophthalmol Vis Sci. 1998;39(3):592–602.PubMedGoogle Scholar
  41. 41.
    Wen R, Tao W, Li Y, Sieving PA. CNTF and retina. Prog Retin Eye Res. 2012;31(2):136–51.PubMedCrossRefGoogle Scholar
  42. 42.
    Dittrich F, Thoenen H, Sendtner M. Ciliary neurotrophic factor: pharmacokinetics and acute-phase response in rat. Ann Neurol. 1994;35(2):151–63.PubMedCrossRefGoogle Scholar
  43. 43.
    Bush RA, Lei B, Tao W, Raz D, Chan CC, Cox TA, Santos-Muffley M, Sieving PA. Encapsulated cell-based intraocular delivery of ciliary neurotrophic factor in normal rabbit: dose-dependent effects on ERG and retinal histology. Invest Ophthalmol Vis Sci. 2004;45(7):2420–30.PubMedCrossRefGoogle Scholar
  44. 44.
    Srivastava A, Lusby EW, Berns KI. Nucleotide sequence and organization of the adeno-associated virus 2 genome. J Virol. 1983;45(2):555–64.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Maguire AM, Simonelli F, Pierce EA, et al. Safety and efficacy of gene transfer for Leber’s congenital amaurosis. N Engl J Med. 2008;358(21):2240–8.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Cideciyan AV, Hauswirth WW, Aleman TS, et al. Human RPE65 gene therapy for Leber congenital amaurosis: persistence of early visual improvements and safety at 1 year. Hum Gene Ther. 2009;20(9):999–1004.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Acland GM, Aguirre GD, Ray J, et al. Gene therapy restores vision in a canine model of childhood blindness. Nat Genet. 2001;28(1):92–5.PubMedGoogle Scholar
  48. 48.
    Acland GM, Aguirre GD, Bennett J, et al. Long-term restoration of rod and cone vision by single dose rAAV-mediated gene transfer to the retina in a canine model of childhood blindness. Mol Ther. 2005;12(6):1072–82.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Kong J, Kim S-R, Binley K, et al. Correction of the disease phenotype in the mouse model of Stargardt disease by lentiviral gene therapy. Gene Ther. 2008;15(19):1311–20.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Jacobson SG, Cideciyan AV, Ratnakaram R, et al. Gene therapy for leber congenital amaurosis caused by RPE65 mutations: safety and efficacy in 15 children and adults followed up to 3 years. Arch Ophthalmol. 2012;130(1):9–24.PubMedCrossRefGoogle Scholar
  51. 51.
    Dudus L, Anand V, Acland GM, et al. Persistent transgene product in retina, optic nerve and brain after intraocular injection of rAAV. Vis Res. 1999;39(15):2545–53.PubMedCrossRefGoogle Scholar
  52. 52.
    Liang FQ, Aleman TS, Dejneka NS, et al. Long-term protection of retinal structure but not function using RAAV.CNTF in animal models of retinitis pigmentosa. Mol Ther. 2001;4(5):461–72.PubMedCrossRefGoogle Scholar
  53. 53.
    Bainbridge JW, Mistry A, Schlichtenbrede FC, et al. AAV-mediated transduction of rod and cone photoreceptors in the canine retina. Gene Ther. 2003;10(16):1336–44.PubMedCrossRefGoogle Scholar
  54. 54.
    Stieger K, Colle MA, Dubreil L, et al. Subretinal delivery of recombinant AAV serotype 8 vector in dogs results in gene transfer to neurons in the brain. Mol Ther. 2008;16(5):916–23.PubMedCrossRefGoogle Scholar
  55. 55.
    Provost N, Le Meur G, Weber M, et al. Biodistribution of rAAV vectors following intraocular administration: evidence for the presence and persistence of vector DNA in the optic nerve and in the brain. Mol Ther. 2005;11(2):275–83.PubMedCrossRefGoogle Scholar
  56. 56.
    Cideciyan AV, Aguirre GK, Jacobson SG, et al. Pseudo-fovea formation after gene therapy for RPE65-LCA. Invest Ophthalmol Vis Sci. 2014;56(1):526–37.PubMedCrossRefGoogle Scholar
  57. 57.
    Komáromy AM, Alexander JJ, Rowlan JS, et al. Gene therapy rescues cone function in congenital achromatopsia. Hum Mol Genet. 2010;19(13):2581–93.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Carvalho LS, Xu J, Pearson RA, et al. Long-term and age-dependent restoration of visual function in a mouse model of CNGB3-associated achromatopsia following gene therapy. Hum Mol Genet. 2011;20(16):3161–75.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Wen R, Tao W, Luo L, et al. Regeneration of cone outer segments induced by CNTF. Adv Exp Med Biol. 2012;723:93–9. doi: 10.1007/978-1-4614-0631-0_13.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Komáromy AM, Rowlan JS, Corr AT, et al. Transient photoreceptor deconstruction by CNTF enhances rAAV-mediated cone functional rescue in late stage CNGB3-achromatopsia. Mol Ther. 2013;21(6):1131–41.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Narfström K, Bragadóttir R, Redmond TM, Rakoczy PE, van Veen T, Bruun A. Functional and structural evaluation after AAV.RPE65 gene transfer in the canine model of Leber’s congenital amaurosis. Adv Exp Med Biol. 2003;533:423–30.PubMedCrossRefGoogle Scholar
  62. 62.
    Maguire AM, High KA, Auricchio A, et al. Age-dependent effects of RPE65 gene therapy for Leber’s congenital amaurosis: a phase 1 dose-escalation trial. Lancet. 2009;374(9701):1597–605.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    MacLaren RE, Pearson RA, MacNeil A, et al. Retinal repair by transplantation of photoreceptor precursors. Nature. 2006;444(7116):203–7.PubMedCrossRefGoogle Scholar
  64. 64.
    Pearson RA, Barber AC, Rizzi M, et al. Restoration of vision after transplantation of photoreceptors. Nature. 2012;485(7396):99–103.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Seiler MJ, Jones BW, Aramant RB, et al. Computational molecular phenotyping of retinal sheet transplants to rats with retinal degeneration. Eur J Neurosci. 2012;35(11):1692–704.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    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.PubMedCrossRefGoogle Scholar
  67. 67.
    Cao J, Murat C, An W, et al. Human umbilical tissue-derived cells rescue retinal pigment epithelium dysfunction in retinal degeneration. Stem Cells. 2016;34(2):367–79. doi: 10.1002/stem.2239.PubMedCrossRefGoogle Scholar
  68. 68.
    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. doi: 10.1016/S0140-6736(14)61376-3.PubMedCrossRefGoogle Scholar
  69. 69.
    Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663–76.PubMedCrossRefGoogle Scholar
  70. 70.
    Reichman S, Terray A, Slembrouck A, et al. From confluent human iPS cells to self-forming neural retina and retinal pigmented epithelium. Proc Natl Acad Sci U S A. 2014;111(23):8518–23.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Buchholz DE, Hikita ST, Rowland TJ, Friedrich AM, Hinman CR, Johnson LV, Clegg DO. Derivation of functional retinal pigmented epithelium from induced pluripotent stem cells. Stem Cells. 2009;27(10):2427–34.PubMedCrossRefGoogle Scholar
  72. 72.
    Kokkinaki M, Sahibzada N, Golestaneh N. Human induced pluripotent stem-derived retinal pigment epithelium (RPE) cells exhibit ion transport, membrane potential, polarized vascular endothelial growth factor secretion, and gene expression pattern similar to native RPE. Stem Cells. 2011;29(5):825–35.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Zhong X, Gutierrez C, Xue T, et al. Generation of three-dimensional retinal tissue with functional photoreceptors from human iPSCs. Nat Commun. 2014;5:4047.PubMedPubMedCentralGoogle Scholar
  74. 74.
    Li Y, Tsai YT, Hsu CW, et al. Long-term safety and efficacy of human-induced pluripotent stem cell (iPS) grafts in a preclinical model of retinitis pigmentosa. Mol Med. 2012;18:1312–9.PubMedPubMedCentralGoogle Scholar
  75. 75.
    Emerich DF, Thanos CG. NT-501: an ophthalmic implant of polymer-encapsulated ciliary neurotrophic factor-producing cells. Curr Opin Mol Ther. 2008;10:506–15.PubMedGoogle Scholar
  76. 76.
    Emerich DF, Thanos CG. Intracompartmental delivery of CNTF as therapy for Huntington’s disease and retinitis pigmentosa. Curr Gene Ther. 2006;6:147–59. doi: 10.2174/156652306775515547.PubMedCrossRefGoogle Scholar
  77. 77.
    Thanos CG, Calafiore R, Basta G, et al. Formulating the alginate-polyornithine biocapsule for prolonged stability: evaluation of composition and manufacturing technique. J Biomed Mater Res A. 2007;83:216–24. doi: 10.1002/jbm.a.31472.PubMedCrossRefGoogle Scholar
  78. 78.
    de Groot M, Schuurs TA, van Schilfgaarde R. Causes of limited survival of microencapsulated pancreatic islet grafts. J Surg Res. 2004;121(1):141–50.PubMedCrossRefGoogle Scholar
  79. 79.
    Bretzel RG, Jahr H, Eckhard M, Martin I, Winter D, Brendel MD. Islet cell transplantation today. Langenbeck’s Arch Surg. 2007;392(3):239–53.CrossRefGoogle Scholar
  80. 80.
    Dunn KC, Aotaki-Keen AE, Putkey FR, Hjelmeland LM. ARPE-19, a human retinal pigment epithelial cell line with differentiated properties. Exp Eye Res. 1996;62(2):155–69.PubMedCrossRefGoogle Scholar
  81. 81.
    Singh PH. Structure-performance-fouling studies of polysulfone microfiltration hollow fiber membranes. Bull Mater Sci. 2012;35(5):817–22.CrossRefGoogle Scholar
  82. 82.
    Rhee KD, Nusinowitz S, Chao K, Yu F, Bok D, Yang XJ. CNTF-mediated protection of photoreceptors requires initial activation of the cytokine receptor gp130 in Müller glial cells. Proc Natl Acad Sci U S A. 2013;110(47):E4520–9.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Bok D, Yasumura D, Matthes MT, et al. Effects of adeno-associated virus-vectored ciliary neurotrophic factor on retinal structure and function in mice with a P216L rds/peripherin mutation. Exp Eye Res. 2002;74(6):719–35.PubMedCrossRefGoogle Scholar
  84. 84.
    Liu C, Li Y, Peng M, Laties AM, Wen R. Activation of caspase-3 in the retina of transgenic rats with the rhodopsin mutation s334ter during photoreceptor degeneration. J Neurosci. 1999;19(12):4778–85.PubMedGoogle Scholar
  85. 85.
    Tao W, Wen R, Goddard MB, et al. Encapsulated cell-based delivery of CNTF reduces photoreceptor degeneration in animal models of retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2002;43(10):3292–8.PubMedGoogle Scholar
  86. 86.
    Zhang K, Hopkins JJ, Heier JS, et al. Ciliary neurotrophic factor delivered by encapsulated cell intraocular implants for treatment of geographic atrophy in age-related macular degeneration. Proc Natl Acad Sci U S A. 2011;108(15):6241–5.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Kauper K, McGovern C, Sherman S, 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. 2012;53(12):7484–91.PubMedCrossRefGoogle Scholar
  88. 88.
    Kauper K, McGovern C, Stabilia P, et al. Continuous intraocular drug delivery over 5 1/2 years: ciliary neurotrophic factor (CNTF) production by encapsulated cell technology implants treating patients with retinitis pigmentosa and geographic atrophy. Invest Ophthalmol Vis Sci. 2013;54(15):3295.Google Scholar
  89. 89.
    Talcott KE, Ratnam K, Sundquist SM, et al. Longitudinal study of cone photoreceptors during retinal degeneration and in response to ciliary neurotrophic factor treatment. Invest Ophthalmol Vis Sci. 2011;52(5):2219–26.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Nadal-Nicolás FM, Sobrado-Calvo P, Jiménez-López M, Vidal-Sanz M, Agudo-Barriuso M. Long-term effect of optic nerve axotomy on the retinal ganglion cell layer. Invest Ophthalmol Vis Sci. 2015;56(10):6095–112.PubMedCrossRefGoogle Scholar
  91. 91.
    Adler R. Ciliary neurotrophic factor as an injury factor. Curr Opin Neurobiol. 1993;3(5):785–9.PubMedCrossRefGoogle Scholar
  92. 92.
    Usher L, Johnstone A, Erturk A, et al. A chemical screen identifies novel compounds that overcome glial-mediated inhibition of neuronal regeneration. J Neurosci. 2010;30(13):4693–706.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Charbel Issa P, Gillies MC, Chew EY, Bird AC, Heeren TF, Peto T, Holz FG, Scholl HP. Macular telangiectasia type 2. Prog Retin Eye Res. 2013;34:49–77.PubMedCrossRefGoogle Scholar
  94. 94.
    Gass JD, Blodi BA. Idiopathic juxtafoveolar retinal telangiectasis. Update of classification and follow-up study. Ophthalmology. 1993;100(10):1536–46.PubMedCrossRefGoogle Scholar
  95. 95.
    Yannuzzi LA, Bardal AM, Freund KB, Chen KJ, Eandi CM, Blodi B. Idiopathic macular telangiectasia. Arch Ophthalmol. 2006;124(4):450–60.PubMedCrossRefGoogle Scholar
  96. 96.
    Shen W, Fruttiger M, Zhu L, Chung SH, Barnett NL, Kirk JK, Lee S, Coorey NJ, Killingsworth M, Sherman LS, Gillies MC. Conditional Müllercell ablation causes independent neuronal and vascular pathologies in a novel transgenic model. J Neurosci. 2012;32(45):15715–27.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Joyal JS, Sun Y, Gantner ML, et al. Retinal lipid and glucose metabolism dictates angiogenesis through the lipid sensor Ffar1. Nat Med. 2016;22(4):439–45.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Dorrell MI, Aguilar E, Jacobson R, et al. Antioxidant or neurotrophic factor treatment preserves function in a mouse model of neovascularization-associated oxidative stress. J Clin Invest. 2009;119(3):611–23.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Rangaswamy NV, Patel HM, Locke KG, Hood DC, Birch DG. A comparison of visual field sensitivity to photoreceptor thickness in retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2010;51(8):4213–9.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Park SJ, Woo SJ, Park KH, Hwang JM, Chung H. Morphologic photoreceptor abnormality in occult macular dystrophy on spectral-domain optical coherence tomography. Invest Ophthalmol Vis Sci. 2010;51(7):3673–9.PubMedCrossRefGoogle Scholar
  101. 101.
    Holz FG, Schmitz-Valckenberg S, Fleckenstein M. Recent developments in the treatment of age-related macular degeneration. J Clin Invest. 2014;124(4):1430–8.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    CATT Research Group, Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, Jaffe GJ. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011;364(20):1897–908.CrossRefGoogle Scholar
  103. 103.
    Rofagha S, Bhisitkul RB, Boyer DS, Sadda SR, Zhang K, SEVEN-UP Study Group. Seven-year outcomes in ranibizumab-treated patients in ANCHOR, MARINA, and HORIZON: a multicenter cohort study (SEVEN-UP). Ophthalmology. 2013;120(11):2292–9.PubMedCrossRefGoogle Scholar
  104. 104.
    Essex RW, Nguyen V, Walton R, et al. Fight Retinal Blindness Study Group. Treatment patterns and visual outcomes during the maintenance phase of treat-and-extend therapy for age-related macular degeneration. Ophthalmology. 2016;123(11):2393–400. pii: S0161-6420(16)30661-3.Google Scholar
  105. 105.
    Rivera M, Nystuen A, Kauper K, Lelis A, Orecchio LD, Elliott S, Stabila P. Analysis of binding affinity and inhibitory capacity of NT-503 produced VEGF antagonist compared to aflibercept. Invest Ophthalmol Vis Sci. 2015;56(7):228.Google Scholar
  106. 106.
    Johnson C. NT-503 Clinical study report NCT02228304, [Neurotech internal report]. 2016 (Unpublished).Google Scholar
  107. 107.
    Holz FG, Korobelnik JF, Lanzetta P, et al. The effects of a flexible visual acuity-driven ranibizumab treatment regimen in age-related macular degeneration: outcomes of a drug and disease model. Invest Ophthalmol Vis Sci. 2010;51(1):405–12.PubMedCrossRefGoogle Scholar

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© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Neurotech Pharmaceuticals, Inc.CumberlandUSA

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