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CRISPR in the Retina: Evaluation of Future Potential

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Precision Medicine, CRISPR, and Genome Engineering

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1016))

Abstract

Clustered regularly interspaced short palindromic repeats (CRISPR) has been gaining widespread attention for its ability for targeted genome surgery. In treating inherited retinal degenerations, gene therapies have had varied results; the ones effective in restoring eye sight are limited by transiency in its effect. Genome surgery, however, is a solution that could potentially provide the eye with permanent healthy cells. As retinal degenerations are irreversible and the retina has little regenerative potential, permanent healthy cells are vital for vision. Since the retina is anatomically accessible and capable of being monitored in vivo, the retina is a prime location for novel therapies. CRISPR technology can be used to make corrections directly in vivo as well as ex vivo of stem cells for transplantation. Current standard of care includes genetic testing for causative mutations in expectation of this potential. This chapter explores future potential and strategies for retinal degenerative disease correction via CRISPR and its limitations.

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References

  1. Sengillo JD, Justus S, Tsai YT, Cabral T, Tsang SH. Gene and cell-based therapies for inherited retinal disorders: an update. Am J Med Genet C Semin Med Genet. 2016;172:349–66. doi:10.1002/ajmg.c.31534.

    Article  PubMed  Google Scholar 

  2. Peyman GA, et al. A technique for retinal pigment epithelium transplantation for age-related macular degeneration secondary to extensive subfoveal scarring. Ophthalmic Surg. 1991;22:102–8.

    CAS  PubMed  Google Scholar 

  3. Tezel TH, Kaplan HJ, Del Priore LV. Fate of human retinal pigment epithelial cells seeded onto layers of human Bruch’s membrane. Invest Ophthalmol Vis Sci. 1999;40:467–76.

    CAS  PubMed  Google Scholar 

  4. Crafoord S, Algvere PV, Kopp ED, Seregard S. Cyclosporine treatment of RPE allografts in the rabbit subretinal space. Acta Ophthalmol Scand. 2000;78:122–9.

    Article  CAS  PubMed  Google Scholar 

  5. Hu Y, et al. Autologous transplantation of RPE with partial-thickness choroid after mechanical debridement of Bruch membrane in the rabbit. Invest Ophthalmol Vis Sci. 2008;49:3185–92. doi:10.1167/iovs.07-1299.

    Article  PubMed  Google Scholar 

  6. Pearson RA, et al. Restoration of vision after transplantation of photoreceptors. Nature. 2012;485:99–103. doi:10.1038/nature10997.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Schwartz SD, 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;385:509–16. doi:10.1016/S0140-6736(14)61376-3.

    Article  PubMed  Google Scholar 

  8. Tsang SH. Stem cell biology and regenerative medicine in ophthalmology. New York: Humana Press; 2013.

    Book  Google Scholar 

  9. Lin MK, Tsai YT, Tsang SH. Emerging treatments for retinitis pigmentosa: genes and stem cells, as well as new electronic and medical therapies, are gaining ground. Retin Physician. 2015;12:52–70.

    PubMed  PubMed Central  Google Scholar 

  10. Li Y, et al. Gene therapy in patient-specific stem cell lines and a preclinical model of retinitis pigmentosa with membrane frizzled-related protein defects. Mol Ther. 2014;22:1688–97. doi:10.1038/mt.2014.100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663–76. doi:10.1016/j.cell.2006.07.024.

    Article  CAS  PubMed  Google Scholar 

  12. Dow LE. Modeling disease in vivo with CRISPR/Cas9. Trends Mol Med. 2015;21:609–21. doi:10.1016/j.molmed.2015.07.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Cabral T, et al. CRISPR applications in ophthalmologic genome surgery. Curr Opin Ophthalmol. 2017;28:252. doi:10.1097/ICU.0000000000000359.

    Article  PubMed  Google Scholar 

  14. Zheng A, Li Y, Tsang SH. Personalized therapeutic strategies for patients with retinitis pigmentosa. Expert Opin Biol Ther. 2015;15:391–402. doi:10.1517/14712598.2015.1006192.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Yang T, Justus S, Li Y, Tsang SH. BEST1: the best target for gene and cell therapies. Mol Ther. 2015;23:1805–9. doi:10.1038/mt.2015.177.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Rosenberg EA, Sperazza LC. The visually impaired patient. Am Fam Physician. 2008;77:1431–6.

    PubMed  Google Scholar 

  17. Moraes F, Goes A. A decade of human genome project conclusion: scientific diffusion about our genome knowledge. Biochem Mol Biol Educ. 2016;44:215–23. doi:10.1002/bmb.20952.

    Article  CAS  PubMed  Google Scholar 

  18. Ponten F, Schwenk JM, Asplund A, Edqvist PH. The human protein atlas as a proteomic resource for biomarker discovery. J Intern Med. 2011;270:428–46. doi:10.1111/j.1365-2796.2011.02427.x.

    Article  CAS  PubMed  Google Scholar 

  19. Austin CP. The impact of the completed human genome sequence on the development of novel therapeutics for human disease. Annu Rev Med. 2004;55:1–13. doi:10.1146/annurev.med.55.091902.104426.

    Article  CAS  PubMed  Google Scholar 

  20. Rabbani B, Mahdieh N, Hosomichi K, Nakaoka H, Inoue I. Next-generation sequencing: impact of exome sequencing in characterizing Mendelian disorders. J Hum Genet. 2012;57:621–32. doi:10.1038/jhg.2012.91.

    Article  CAS  PubMed  Google Scholar 

  21. Metzker ML. Sequencing technologies—the next generation. Nat Rev Genet. 2010;11:31–46. doi:10.1038/nrg2626.

    Article  CAS  PubMed  Google Scholar 

  22. The Cost of Sequencing a Human Genome. https://www.genome.gov/sequencingcosts/.

  23. Service RF. Gene sequencing. The race for the $1000 genome. Science. 2006;311:1544–6. doi:10.1126/science.311.5767.1544.

    Article  CAS  PubMed  Google Scholar 

  24. Bick D, Dimmock D. Whole exome and whole genome sequencing. Curr Opin Pediatr. 2011;23:594–600. doi:10.1097/MOP.0b013e32834b20ec.

    Article  PubMed  Google Scholar 

  25. van El CG, et al. Whole-genome sequencing in health care. Recommendations of the European Society of Human Genetics. Eur J Hum Genet. 2013;21(Suppl 1):S1–5.

    PubMed  PubMed Central  Google Scholar 

  26. Ashley EA, et al. Clinical assessment incorporating a personal genome. Lancet. 2010;375:1525–35. doi:10.1016/S0140-6736(10)60452-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wade CH, Tarini BA, Wilfond BS. Growing up in the genomic era: implications of whole-genome sequencing for children, families, and pediatric practice. Annu Rev Genomics Hum Genet. 2013;14:535–55. doi:10.1146/annurev-genom-091212-153425.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Sengillo JD, Justus S, Cabral T, Tsang SH. Correction of monogenic and common retinal disorders with gene therapy. Genes (Basel). 2017;8. doi:10.3390/genes8020053.

  29. Daiger SP. Retnet: summaries of genes and loci causing retinal diseases. https://sph.uth.edu/RetNet/sum-dis.htm.

  30. Cepko CL, Vandenberghe LH. Retinal gene therapy coming of age. Hum Gene Ther. 2013;24:242–4. doi:10.1089/hum.2013.050.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Bennett J, et al. Safety and durability of effect of contralateral-eye administration of AAV2 gene therapy in patients with childhood-onset blindness caused by RPE65 mutations: a follow-on phase 1 trial. Lancet. 2016;388:661–72. doi:10.1016/S0140-6736(16)30371-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. MacLaren RE, et al. Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial. Lancet. 2014;383:1129–37. doi:10.1016/S0140-6736(13)62117-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Conlon TJ, et al. Preclinical potency and safety studies of an AAV2-mediated gene therapy vector for the treatment of MERTK associated retinitis pigmentosa. Hum Gene Ther Clin Dev. 2013;24:23–8. doi:10.1089/humc.2013.037.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ghazi NG, et al. Treatment of retinitis pigmentosa due to MERTK mutations by ocular subretinal injection of adeno-associated virus gene vector: results of a phase I trial. Hum Genet. 2016;135:327–43. doi:10.1007/s00439-016-1637-y.

    Article  CAS  PubMed  Google Scholar 

  35. Feuer WJ, et al. Gene therapy for leber hereditary optic neuropathy: initial results. Ophthalmology. 2016;123:558–70. doi:10.1016/j.ophtha.2015.10.025.

    Article  PubMed  Google Scholar 

  36. Bainbridge JW, et al. Long-term effect of gene therapy on Leber’s congenital amaurosis. N Engl J Med. 2015;372:1887–97. doi:10.1056/NEJMoa1414221.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Bassuk AG, Zheng A, Li Y, Tsang SH, Mahajan VB. Precision medicine: genetic repair of retinitis pigmentosa in patient-derived stem cells. Sci Rep. 2016;6:19969. doi:10.1038/srep19969.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Cramer AO, MacLaren RE. Translating induced pluripotent stem cells from bench to bedside: application to retinal diseases. Curr Gene Ther. 2013;13:139–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lin T, et al. A chemical platform for improved induction of human iPSCs. Nat Methods. 2009;6:805–8. doi:10.1038/nmeth.1393.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Bassuk AG, Sujirakul T, Tsang SH, Mahajan VB. A novel RPGR mutation masquerading as Stargardt disease. Br J Ophthalmol. 2014;98:709–11. doi:10.1136/bjophthalmol-2013-304822.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Kirschner R, et al. DNA sequence comparison of human and mouse retinitis pigmentosa GTPase regulator (RPGR) identifies tissue-specific exons and putative regulatory elements. Hum Genet. 2001;109:271–8. doi:10.1007/s004390100572.

    Article  CAS  PubMed  Google Scholar 

  42. Wu WH, et al. CRISPR repair reveals causative mutation in a preclinical model of retinitis pigmentosa. Mol Ther. 2016;24:1388–94. doi:10.1038/mt.2016.107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Bowes C, et al. Retinal degeneration in the rd mouse is caused by a defect in the beta subunit of rod cGMP-phosphodiesterase. Nature. 1990;347:677–80. doi:10.1038/347677a0.

    Article  CAS  PubMed  Google Scholar 

  44. Davis RJ, et al. Therapeutic margins in a novel preclinical model of retinitis pigmentosa. J Neurosci. 2013;33:13475–83. doi:10.1523/JNEUROSCI.0419-13.2013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Koch SF, et al. Halting progressive neurodegeneration in advanced retinitis pigmentosa. J Clin Invest. 2015;125:3704–13. doi:10.1172/JCI82462.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Wert KJ, et al. Functional validation of a human CAPN5 exome variant by lentiviral transduction into mouse retina. Hum Mol Genet. 2014;23:2665–77. doi:10.1093/hmg/ddt661.

    Article  CAS  PubMed  Google Scholar 

  47. Long C, et al. Prevention of muscular dystrophy in mice by CRISPR/Cas9-mediated editing of germline DNA. Science. 2014;345:1184–8. doi:10.1126/science.1254445.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Long C, et al. Postnatal genome editing partially restores dystrophin expression in a mouse model of muscular dystrophy. Science. 2016;351:400–3. doi:10.1126/science.aad5725.

    Article  CAS  PubMed  Google Scholar 

  49. Taylor-Weiner H, Graff Zivin J. Medicine’s wild west—unlicensed stem-cell clinics in the United States. N Engl J Med. 2015;373:985–7. doi:10.1056/NEJMp1504560.

    Article  PubMed  Google Scholar 

  50. Berger I, et al. Global distribution of businesses marketing stem cell-based interventions. Cell Stem Cell. 2016;19:158–62. doi:10.1016/j.stem.2016.07.015.

    Article  CAS  PubMed  Google Scholar 

  51. Boudreault K, Justus S, Lee W, Mahajan VB, Tsang SH. Complication of autologous stem cell transplantation in retinitis pigmentosa. JAMA Ophthalmol. 2016;134:711–2. doi:10.1001/jamaophthalmol.2016.0803.

    Article  PubMed  Google Scholar 

  52. Jonas JB, Witzens-Harig M, Arseniev L, Ho AD. Intravitreal autologous bone-marrow-derived mononuclear cell transplantation. Acta Ophthalmol. 2010;88:e131–2. doi:10.1111/j.1755-3768.2009.01564.x.

    Article  PubMed  Google Scholar 

  53. Arnhold S, Absenger Y, Klein H, Addicks K, Schraermeyer U. Transplantation of bone marrow-derived mesenchymal stem cells rescue photoreceptor cells in the dystrophic retina of the rhodopsin knockout mouse. Graefes Arch Clin Exp Ophthalmol. 2007;245:414–22. doi:10.1007/s00417-006-0382-7.

    Article  CAS  PubMed  Google Scholar 

  54. Jinek M, et al. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science. 2012;337:816–21. doi:10.1126/science.1225829.

    Article  CAS  PubMed  Google Scholar 

  55. Fu Y, et al. High-frequency off-target mutagenesis induced by CRISPR-Cas nucleases in human cells. Nat Biotechnol. 2013;31:822–6. doi:10.1038/nbt.2623.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Tsai SQ, et al. GUIDE-seq enables genome-wide profiling of off-target cleavage by CRISPR-Cas nucleases. Nat Biotechnol. 2015;33:187–97. doi:10.1038/nbt.3117.

    Article  CAS  PubMed  Google Scholar 

  57. Daiger SP, Bowne SJ, Sullivan LS. Perspective on genes and mutations causing retinitis pigmentosa. Arch Ophthalmol. 2007;125:151–8. doi:10.1001/archopht.125.2.151.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Zhang L, et al. Reprogramming metabolism by targeting sirtuin 6 attenuates retinal degeneration. J Clin Invest. 2016;126:4659–73. doi:10.1172/JCI86905.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Hurley JB, Lindsay KJ, Du J. Glucose, lactate, and shuttling of metabolites in vertebrate retinas. J Neurosci Res. 2015;93:1079–92. doi:10.1002/jnr.23583.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Curcio CA, Sloan KR, Kalina RE, Hendrickson AE. Human photoreceptor topography. J Comp Neurol. 1990;292:497–523. doi:10.1002/cne.902920402.

    Article  CAS  PubMed  Google Scholar 

  61. Martinez-Pastor B, Mostoslavsky R. Sirtuins, metabolism, and cancer. Front Pharmacol. 2012;3:22. doi:10.3389/fphar.2012.00022.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324:1029–33. doi:10.1126/science.1160809.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Punzo C, Kornacker K, Cepko CL. Stimulation of the insulin/mTOR pathway delays cone death in a mouse model of retinitis pigmentosa. Nat Neurosci. 2009;12:44–52. doi:10.1038/nn.2234.

    Article  CAS  PubMed  Google Scholar 

  64. Venkatesh A, et al. Activated mTORC1 promotes long-term cone survival in retinitis pigmentosa mice. J Clin Invest. 2015;125:1446–58. doi:10.1172/JCI79766.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Yang H, et al. One-step generation of mice carrying reporter and conditional alleles by CRISPR/Cas-mediated genome engineering. Cell. 2013;154:1370–9. doi:10.1016/j.cell.2013.08.022.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Peng Y, et al. Making designer mutants in model organisms. Development. 2014;141:4042–54. doi:10.1242/dev.102186.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Hess GT, et al. Directed evolution using dCas9-targeted somatic hypermutation in mammalian cells. Nat Methods. 2016;13:1036–42. doi:10.1038/nmeth.4038.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Odegard VH, Schatz DG. Targeting of somatic hypermutation. Nat Rev Immunol. 2006;6:573–83. doi:10.1038/nri1896.

    Article  CAS  PubMed  Google Scholar 

  69. Di Noia JM, Neuberger MS. Molecular mechanisms of antibody somatic hypermutation. Annu Rev Biochem. 2007;76:1–22. doi:10.1146/annurev.biochem.76.061705.090740.

    Article  PubMed  Google Scholar 

  70. Chaudhuri J, et al. Transcription-targeted DNA deamination by the AID antibody diversification enzyme. Nature. 2003;422:726–30. doi:10.1038/nature01574.

    Article  CAS  PubMed  Google Scholar 

  71. Cong L, et al. Multiplex genome engineering using CRISPR/Cas systems. Science. 2013;339:819–23. doi:10.1126/science.1231143.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Mali P, et al. RNA-guided human genome engineering via Cas9. Science. 2013;339:823–6. doi:10.1126/science.1232033.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Author information

Authors and Affiliations

  1. Institute of Human Nutrition, College of Physicians and Surgeons, Columbia University, New York, NY, USA

    Galaxy Y. Cho B.A., M.S. & Stephen H. Tsang M.D., Ph.D.

  2. Department of Ophthalmology, Columbia University, New York, NY, USA

    Galaxy Y. Cho B.A., M.S., Sally Justus B.A., Jesse D. Sengillo B.S. & Stephen H. Tsang M.D., Ph.D.

  3. Jonas Children’s Vision Care, and Bernard & Shirlee Brown Glaucoma Laboratory, Columbia University, New York, NY, USA

    Galaxy Y. Cho B.A., M.S., Sally Justus B.A., Jesse D. Sengillo B.S. & Stephen H. Tsang M.D., Ph.D.

  4. State University of New York Downstate Medical Center, Brooklyn, NY, USA

    Jesse D. Sengillo B.S.

  5. Department of Pathology and Cell Biology, Columbia University, New York, NY, USA

    Stephen H. Tsang M.D., Ph.D.

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  1. Galaxy Y. Cho B.A., M.S.
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  2. Sally Justus B.A.
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  3. Jesse D. Sengillo B.S.
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  4. Stephen H. Tsang M.D., Ph.D.
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Corresponding author

Correspondence to Stephen H. Tsang M.D., Ph.D. .

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Editors and Affiliations

  1. Departments of Ophthalmology, Pathology & Cell Biology and Biomedical Engineering, Institute of Human Nutrition, Columbia Stem Cell Initiative, Herbert Irving Comprehensive Cancer Center, Graduate Program in Neurobiology & Behavior, Columbia University, New York, New York, USA

    Stephen H. Tsang

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Cho, G.Y., Justus, S., Sengillo, J.D., Tsang, S.H. (2017). CRISPR in the Retina: Evaluation of Future Potential. In: Tsang, S. (eds) Precision Medicine, CRISPR, and Genome Engineering. Advances in Experimental Medicine and Biology, vol 1016. Springer, Cham. https://doi.org/10.1007/978-3-319-63904-8_8

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