Advertisement

Prospects and modalities for the treatment of genetic ocular anomalies

  • Cheryl Y. Gregory-EvansEmail author
  • Xia Wang
  • Kevin Gregory-Evans
Original Investigation
Part of the following topical collections:
  1. Eye Genetics
  2. Eye Genetics
  3. Eye Genetics

Abstract

Over the last three decades, genetic studies have made great strides toward the identification of genes and genetic mechanisms underlying congenital disorders of the eye. However, despite the vast knowledge available this has not translated into treatments to prevent or repair the damage in the clinical setting. Recently, new research in technologies, such as tissue regeneration, next generation designer drugs, and genome editing, have become available for some genetic disorders that might be applicable to congenital ocular diseases in the near future. Here, we provide an overview of the emerging therapeutic modalities and the future prospects they hold for debilitating ocular defects.

Notes

Compliance with ethical standards

Conflict of interest

The authors declare there is no conflict of interest.

References

  1. Adler R, Canto-Soler MV (2007) Molecular mechanisms of optic vesicle development: complexities, ambiguities and controversies. Dev Biol 305:1–13CrossRefGoogle Scholar
  2. Ahmad S, Stewart R, Yung S, Kolli S, Armstrong L, Stojkovuic M et al (2007) Differentiation of human embryonic stem cells into corneal epithelial-like cells by in vitro replication of the corneal epithelial stem cell niche. Stem Cells 25:1145–1155CrossRefGoogle Scholar
  3. Ahmad S, Osei-Bempong C, Reza D, Jurkunas U (2010) The culture and transplantation of human limbal stem cells. J Cell Physiol 225:15–19CrossRefGoogle Scholar
  4. Allergan and Editas Medicine enter into strategic R&D alliance to discover and develop CRISPR genome editing medicines for eye diseases. Allergan Press Releases; 2017; March 14, 2017. https://www.allergan.com/news/news/thomson-reuters/allergan-and-editas-medicine-enter-into-strategic
  5. Bassuk AG, Zheng A, Li Y, Tsang SH, Mahajan VB (2016) Precision medicine: genetic repair of retinitis pigmentosa in patient-derived stem cells. Sci Rep 6:19969CrossRefGoogle Scholar
  6. Bhatia B, Singhal S, Lawrence JM, Khaw PT, Limb GA (2009) Distribution of Muller stem cells within the neural retina: evidence for the existence of a ciliary margin-like zone in the adult human eye. Exp Eye Res 89:373–382CrossRefGoogle Scholar
  7. Brennan D, Giles S (2014) Ocular involvement in fetal alcohol spectrum disorder: a review. Curr Pharm Des 20:5377–5387CrossRefGoogle Scholar
  8. Brzeszczynska J, Samuel K, Greenhough S, Ramaesh K, Dhillon B, Hay DC et al (2014) Differentiation and molecular profiling of human embryonic stem cell-derived corneal epithelial cells. Int J Mol Med 33:1597–1606CrossRefGoogle Scholar
  9. Burnight ER, Giacalone JC, Cooke JA, Thompson JR, Bohrer LR, Chirco KR et al (2018) CRISPR-Cas9 genome engineering: treating inherited retinal degeneration. Prog Retin Eye Res Mar 22,  https://doi.org/10.1016/j.preteyeres.2018.03.003
  10. Cevkl A, Mitton KP (2010) Epigenetic regulatory mechanisms in vertebrate eye development and disease. Heredity 105:135–151CrossRefGoogle Scholar
  11. Chassaing N, Causse A, Vigouroux A, Delahaye A, Alessandri JL, Boespflug-Tanguy O et al (2014) Molecular findings and clinical data in a cohort of 150 patients with anophthalmia/microphthalmia. Clin Genet 86:326–334CrossRefGoogle Scholar
  12. Chou CM, Nelson C, Tarle SA, Pribila JT, Bardakjian T, Woods S et al (2015) Biochemical basis for dominant inheritance, variable penetrance, and maternal effects in RBP4 congenital eye disease. Cell 161:634–646CrossRefGoogle Scholar
  13. Das AV, Mallya KB, Zhao X, Ahmad F, Bhattacharya S, Thoreson WB et al (2006) Neural stem cell properties of Muller glia in the mammalian retina: regulation by Notch and Wnt. signaling Dev Biol 299:283–302CrossRefGoogle Scholar
  14. Drivas TG, Holzbaur EL, Bennett J (2013) Disruption of CEP290 microtubule/membrane-binding domains causes retinal degeneration. J Clin Invest 123:4525–4539CrossRefGoogle Scholar
  15. Dua HS, Azuara-Blanco A (2000) Limbal stem cells of the corneal epithelium. Surv Ophthalmol 44:415–425CrossRefGoogle Scholar
  16. Ducker GS, Rabinowitz JD (2017) One-carbon metabolism in health and disease. Cell Metab 25:27–42CrossRefGoogle Scholar
  17. Dunlevy LPE, Burren KA, Mills K, Chitty LS, Copp AJ, Green NDE (2006) Integrity of the methylation cycle is essential for mammalian neural tube closure. Birth Defects Res A Clin Mol Teratol 76:544–552CrossRefGoogle Scholar
  18. Eastlake K, Heywood WE, Tracey-White D, Aquino E, Bliss E, Vasta GR et al (2017) Comparison of proteomic profiles in zebrafish retina during experimental degeneration and regeneration. Sci Rep 7:44601CrossRefGoogle Scholar
  19. Egli D, Zuccaro MV, Kosicki M, Church GM, Bradley A, Jasin M (2018) Inter-homogue repair in fertilized human eggs? Nature 560:E5–E7CrossRefGoogle Scholar
  20. Foster JW, Wahlin K, Adams SM, Birk DE, Zack DJ, Chakravarti S (2017) Cornea organoids from human induced pluripotent stem cells. Sci Rep 7:41286CrossRefGoogle Scholar
  21. Friso S, Choi SW, Girelli D, Mason JB, Dolnikowski GG, Bagley PJ et al (2002) A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status. Proc Natl Acad Sci USA 99:5606–5611CrossRefGoogle Scholar
  22. Goldmann T, Overlack N, Moller F, Belekhov V, van Wyk M, Baasov T et al (2012) A comparative evaluation of NB30, NB54 and PTC124 in translational read-through efficacy for treatment of an USH1C nonsense mutation. EMBO Mol Med 4:1186e1199CrossRefGoogle Scholar
  23. Gonzalez-Hilarion S, Beghyn T, Jia J, Debreuck N, Berte G, Mamchaoui K et al (2012) Rescue of nonsense mutations by amlexanox in human cells. Orphanet J Rare Dis 7:58CrossRefGoogle Scholar
  24. Gore AV, Tomins KA, Iben J, Ma L, Castranova D, Davis AE et al (2018) An epigenetic mechanism for cavefish eye degeneration. Nat Ecol Evol 2:115–1160CrossRefGoogle Scholar
  25. Graw J (2010) Eye development. Curr Top Eye Dev 90:343–386CrossRefGoogle Scholar
  26. Guerin K, Gregory-Evans CY, Hodges MD, Moosajee M, Mackay DS, Gregory-Evans K, Flannery JG (2008) Systemic aminoglycoside treatment in rodent models of retinitis pigmentosa. Exp Eye Res 87:197–207CrossRefGoogle Scholar
  27. Hendrickson A, Possin D, Vajzovic L, Toth CA (2012) Histologic development of the human fovea from midgestation to maturity. Am J Ophthalmol 154:767–778CrossRefGoogle Scholar
  28. Hornby SJ, Ward SJ, Gilbert CE, Dandona L, Foster A, Jones RB (2002) Environmental risk factors in congenital malformations of the eye. Ann Trop Paediatr 22:67–77CrossRefGoogle Scholar
  29. Horvath P, Barrangou R (2010) CRISPR/Cas, the immune system of bacteria and archaea. Science 327:167–170CrossRefGoogle Scholar
  30. Howard M, Frizzell RA, Bedwell DM (1996) Aminoglycoside antibiotics restore CFTR function by overcoming premature stop mutations. Nat Med 2:467–469CrossRefGoogle Scholar
  31. Hu X (2016) CRISPR/Cas9 system and its applications in human hematopoietic cells. Blood Cells Mol Dis 62:6–12CrossRefGoogle Scholar
  32. Joe AW, Yeung SN (2014) Concise review: identifying limbal stem cells: classical concepts and new challenges. Stem Cells Transl Med 3:318–22CrossRefGoogle Scholar
  33. Iismaa SE, Kaidonis X, Nicks AM, Bogush N, Kikuchi K, Naqvi N et al (2018) Comparative regenerative mechanisms across different mammalian tissues. NPJ Regen Med 3:6CrossRefGoogle Scholar
  34. Lawrence JM, Singhal S, Bhatia B et al (2007) MIO-M1 cells and similar Muller glial cell lines derived from adult. Hum Retina Exhib Neural Stem Cell Charact Stem Cells 25:2033–2043Google Scholar
  35. Lee H-L, Dougherty JP (2012) Pharmaceutical therapies to recode nonsense mutations in inherited diseases. Pharmacol Ther 136:227–266CrossRefGoogle Scholar
  36. Leung KY, Pai YJ, Chen Q, Santos C, Calvani E, Sudiwala S et al (2017) Partitioning of one-carbon units in folate and methionine metabolism is essential for neural tube closure. Cell Rep 21:1795–1808CrossRefGoogle Scholar
  37. Lillien L (1994) Neurogenesis in the vertebrate retina. Perspect Dev Neurobiol 2:172–182Google Scholar
  38. Lin H, Ouyang H, Zhu J, Huang S, Liu Z, Chen S et al (2016) Lens regeneration using endogenous stem cells with gain of visual function. Nature 531:323–328CrossRefGoogle Scholar
  39. Linde L, Boelz S, Nissim-Rafinia M, Oren YS, Wilschanski M, Yaacov Y et al (2007) Nonsense-mediated mRNA decay affects nonsense transcript levels and governs response of cystic fibrosis patients to gentamicin. J Clin Invest 117:683–692CrossRefGoogle Scholar
  40. Lust K, Wittbrodt J (2018) Activating the regenerative potential of Müller glia cells in a regeneration-deficient retina. Elife Jan 29;7  https://doi.org/10.7554/eLife.32319
  41. Ma H, Marti-Gutierrez N, Park SW, Wu J, Lee Y, Suzuki K et al (2017) Correction of a pathogenic gene mutation in human embryos. Nature 548:413–419CrossRefGoogle Scholar
  42. Maeder ML, Shen S, Burnight ER, Gloskowski S, Mepani R, Friedland AE et al (2015) Therapeutic correction of an LCA-causing splice defect in the CEP290 gene by CRISPR/Cas-mediated genome editing. Mol Ther 23:S273–S274CrossRefGoogle Scholar
  43. Martin-del-Campo R, Barcenas-Ibarra A, Sifuentes-Romero I, Llera-Herrera R, Garcia-Gasca A (2018) Methylation status of the putative Pax6 promoter in olive ridley sea turtle embryos with eye defects: an initial approach. Mech Dev.  https://doi.org/10.1016/j.mod.2018.08.005. [Epub ahead of print]Google Scholar
  44. Martinez-Navarrete GC, Angulo A, Martin-Nieto J, Cuenca N (2008) Gradual morphogenesis of retinal neurons in the peripheral retinal margin of adult monkeys and humans. J Comp Neurol 511:557–580CrossRefGoogle Scholar
  45. Miller MT, Stromland K (1999) Teratogen update - thalidomide: a review, with a focus on ocular findings and new potential uses. Teratology 60:306–321CrossRefGoogle Scholar
  46. Monje ML, Toda H, Palmer TD (2003) Inflammatory blockade restores adult hippocampal neurogenesis. Science 302:1760–1765CrossRefGoogle Scholar
  47. Moosajee M, Gregory-Evans K, Ellis CD, Seabra MC, Gregory-Evans CY (2008) Translational bypass of nonsense mutations in zebrafish rep1, pax2.1 and lamb1 highlights a viable therapeutic option for untreatable genetic eye disease. Hum Mol Genet 17:3987–4000CrossRefGoogle Scholar
  48. Moosajee M, Tracey-White D, Smart M, Weetall M, Torriano S, da Cruz L et al (2016) Functional rescue of REP1 following treatment with PTC124 and novel derivative PTC-414 in human choroideremia fibroblasts and the nonsense-mediated zebrafish model. Hum Mol Genet 25:3416–3431CrossRefGoogle Scholar
  49. Morscher RJ, Ducker GS, Li SH, Mayer JA, Gitai Z, Sperl W et al (2018) Mitochondrial translation requires folate-dependent tRNA methylation. Nature 554:128–132CrossRefGoogle Scholar
  50. Mort M, Ivanov D, Cooper DN, Chuzhanova NA (2008) A meta-analysis of nonsense mutations causing human genetic disease. Hum Mutat 29:1037–1047CrossRefGoogle Scholar
  51. MRC Vitamin Study Research Group (1991) Prevention of neural tube defects: results of the medical research council vitamin study. Lancet 338:131–137CrossRefGoogle Scholar
  52. National Academies of Sciences, Engineering, and Medicine (2017) Human Genome Editing: Science, Ethics, and Governance. The National Academies Press, Washington.  https://doi.org/10.17226/24623 Google Scholar
  53. Netland PA, Scott ML, Boyle JW, Lauderdale JD (2011) Ocular and systemic findings in a survey of aniridia subjects. J AAPOS 15:562–566CrossRefGoogle Scholar
  54. Neuhaus C, Eisenberger T, Decker C, Nagl S, Blank C, Pfister M et al (2017) Next-generation sequencing reveals the mutational landscape of clinically diagnosed Usher syndrome: copy number variations, phenocopies, a predominant target for translational read-through, and PEX26 mutated in Heimler syndrome. Mol Genet Genomic Med 5:531–552CrossRefGoogle Scholar
  55. Ooto S, Akagi T, Kageyama R, Akita J, Mandai M, Yoshihito Y et al (2004) Potential for neural regeneration after neurotoxic injury in the adult mammalian retina. Proc Natl Acad Sci USA 101:13654–13659CrossRefGoogle Scholar
  56. Padmanabhan N, Jia D, Geary-Joo C, Wu X, Ferguson-Smith AC, Fung E et al (2015) Mutation in folate metabolism causes epigenetic instability and transgenerational effects on development. Cell 155:81–93CrossRefGoogle Scholar
  57. Palhan VB, Chen S, Peng G-H, Tjernberg A, Gamper AM, Fan Y et al (2005) Polyglutamine-expanded ataxin-7 inhibits STAGA histone acetyltransferase activity to producMRCe retinal degeneration. Proc Natl Acad Sci USA 2005 102:8472–8477CrossRefGoogle Scholar
  58. Palmer TD, Takahashi J, Gage FH (1997) The adult rat hippocampus contains primordial neural stem cells. Mol cell Neurosci 8:389–404CrossRefGoogle Scholar
  59. Porter LF, Black GC (2014) Personalized ophthalmology. Clin Genet 86:1–11CrossRefGoogle Scholar
  60. Rahi JS, Cable N (2003) Severe visual impairment and blindness in children in the UK. The Lancet 362:1359–1365CrossRefGoogle Scholar
  61. Rama P, Matuska S, Paganoni G, Spinelli A, De Luca M, Pellegrini G G (2010) Limbal stem-cell therapy and long-term corneal regeneration. N Engl J Med 363:147–155CrossRefGoogle Scholar
  62. Raymond PA, Barthel LK, Bernardos RL, Perkowski JJ (2006) Molecular characterization of retinal stem cells and their niches in adult zebrafish. BMC Dev Biol 6:36CrossRefGoogle Scholar
  63. Rhan RI, O’Keefe M, Kenny D, Nolan L (2007) Changing pattern of childhood blindness. Ir Med J 100:458–461Google Scholar
  64. Sareen D, Saghizadeh M, Ornelas L, Winkler MA, Narwani K, Sahabian et al (2014) Differentiation of human limbal-derived induced pluripotent stem cells into limbal-like epithelium. Stem Cells Transl Med 3:1002–1012CrossRefGoogle Scholar
  65. Schwarz N, Carr A-J, Lane A, Moeller F, Chen LL, Aguila M et al (2015) Translational read-through of the RP2 Arg120stop mutation in patient iPSC-derived retinal pigment epithelium cells. Hum Mol Genet 24:972–986CrossRefGoogle Scholar
  66. Solebo AL, Hammond CJ, Rahi JS (2018) Improving outcomes in congenital cataract. Nature 556:E1–E2CrossRefGoogle Scholar
  67. Spalding KL, Bergmann O, Alkass K, Bernard S, Salehpour M, Huttner HB et al (2013) Dynamics of hippocampal neurogenesis in adult humans. Cell 153:1219–1227CrossRefGoogle Scholar
  68. Sun D (2014) The potential of endogenous neurogenesis for brain repair and regeneration following traumatic brain injury. Neural Regen Res 9:688–692CrossRefGoogle Scholar
  69. Susaimanickam PJ, Maddileti S, Pulimamidi VK, Boyinpally SR, Naik RR, Naik MN et al (2017) Generating minicorneal organoids from human induced pluripotent stem cells. Development 144:2338–2351CrossRefGoogle Scholar
  70. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K et al (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–872CrossRefGoogle Scholar
  71. Tsai Y-T, Wu W-H, Lee T-T, Wu W-P, Xu CL, Park KS et al (2018) Clustered regularly interspaced short palindromic repeats-based genome surgery for the treatment of autosomal dominant retinitis pigmentosa. Ophthalmology 125:1421–1430CrossRefGoogle Scholar
  72. Valensisi C, Andrus C, Buckberry S et al (2017) Epigenomic landscapes of hesc-derived neural rosettes: modeling neural tube formation and diseases. Cell Rep 20:1448–1462CrossRefGoogle Scholar
  73. Wagner KR, Hamed S, Hadley DW (2001) Gentamicin treatment of Duchenne and Becker muscular dystrophy due to nonsense mutations. Ann Neurol 49:706e711CrossRefGoogle Scholar
  74. Wang X, Gregory-Evans CY (2015) Nonsense suppression therapies in ocular genetic diseases. Cell Mol Life Sci 72:1931–1938CrossRefGoogle Scholar
  75. Wang X, Gregory-Evans K, Wasan KM, Sivak O, Shan X, Gregory-Evans CY (2017) Efficacy of postnatal in vivo nonsense suppression therapy in a Pax6 mouse model of aniridia. Mol Ther Nucleic Acids 7:47–428CrossRefGoogle Scholar
  76. Weber KA, Yang W, Carmichael SL, Shaw GM, National Birth Defects Prevention Study (2018) Nutrient intake in women before conception and risks of anophthalmia and microphthalmia in their offspring. Birth Defects Res 110:853–870CrossRefGoogle Scholar
  77. Wetts R, Serbedzija GN, Fraser SE (1989) Cell lineage analysis reveals multipotent precursors in the ciliary margin of the frog retina Dev Biol 136:254–263CrossRefGoogle Scholar
  78. Wiedenheft B, Sternberg SH, Doudna JA (2012) RNA-guided genetic silencing systems in bacteria and archaea. Nature 482:331–338CrossRefGoogle Scholar
  79. Wilde JJ, Petersen JR, Niswander L (2014) Genetic, epigenetic, and environmental contributions to neural tube closure. Annu Rev Genet 48:583–611CrossRefGoogle Scholar
  80. Wu Y, Liang D, Wang Y, Bai M, Tang W, Bao S et al (2013) Correction of a genetic disease in mouse via use of CRISPR-Cas9. Cell Stem Cell 13:659–662CrossRefGoogle Scholar
  81. Zheng S, Xiao L, Liu Y, Wang Y, Cheng L, Zhang J et al (2018) DZNep inhibits H3K27me3 deposition and delays retinal degeneration in the rd1 mice. Cell Death Dis 9:310CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Ophthalmology and Visual SciencesUniversity of British ColumbiaVancouverCanada

Personalised recommendations