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Molecular Therapy for Choroideremia: Pre-clinical and Clinical Progress to Date

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Abstract

Choroideremia is an inherited retinal disease characterised by a degeneration of the light-sensing photoreceptors, supporting retinal pigment epithelium and underlying choroid. Patients present with the same symptoms as those with classic rod-cone dystrophy: (1) night blindness early in life; (2) progressive peripheral visual field loss, and (3) central vision decline with a slow progression to legal blindness. Choroideremia is monogenic and caused by mutations in CHM. Eight clinical trials (three phase 1/2, four phase 2, and one phase 3) have started (four of which are already finished) to evaluate the therapeutic efficacy of gene supplementation mediated by subretinal delivery of an adeno-associated virus serotype 2 (AAV2/2) vector expressing CHM. Furthermore, one phase 1 clinical trial has been initiated to evaluate the efficiency of a novel AAV variant to deliver CHM to the outer retina following intravitreal delivery. Lastly, a non-viral-mediated CHM replacement strategy is currently under development, which could lead to a future clinical trial. Here, we summarise the rationale behind these various studies, as well as any results published to date. The diversity of these trials currently places choroideremia at the forefront of the retinal gene therapy field. As a consequence, the trial outcomes, regardless of the results, have the potential to change the landscape of gene supplementation for inherited retinal diseases.

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References

  1. Grossniklaus HE, Geisert EE, Nickerson JM. Introduction to the retina. Prog Mol Biol Transl Sci. 2015;134:383–96. https://doi.org/10.1016/bs.pmbts.2015.06.001.

    Article  PubMed  Google Scholar 

  2. Sparrow JR, Hicks D, Hamel CP. The retinal pigment epithelium in health and disease. Curr Mol Med. 2010;10:802–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Strauss O. The retinal pigment epithelium in visual function. Physiol Rev. 2005;85:845–81. https://doi.org/10.1152/physrev.00021.2004.

    Article  PubMed  CAS  Google Scholar 

  4. Zhang Y, Wildsoet CF. RPE and choroid mechanisms underlying ocular growth and myopia. Prog Mol Biol Transl Sci. 2015;134:221–40. https://doi.org/10.1016/bs.pmbts.2015.06.014.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Fields MA, Del Priore LV, Adelman RA, Rizzolo LJ. Interactions of the choroid, Bruch’s membrane, retinal pigment epithelium, and neurosensory retina collaborate to form the outer blood–retinal-barrier. Prog Retin Eye Res. 2019. https://doi.org/10.1016/j.preteyeres.2019.100803.

    Article  PubMed  Google Scholar 

  6. Sullivan LS, Daiger SP. Inherited retinal degeneration: exceptional genetic and clinical heterogeneity. Mol Med Today. 1996;2:380–6. https://doi.org/10.1016/s1357-4310(96)10037-x.

    Article  PubMed  CAS  Google Scholar 

  7. Verbakel SK, van Huet RAC, Boon CJF, den Hollander AI, Collin RWJ, Klaver CCW, et al. Non-syndromic retinitis pigmentosa. Prog Retin Eye Res. 2018;66:157–86. https://doi.org/10.1016/j.preteyeres.2018.03.005.

    Article  PubMed  Google Scholar 

  8. Berger W, Kloeckener-Gruissem B, Neidhardt J. The molecular basis of human retinal and vitreoretinal diseases. Prog Retin Eye Res. 2010;29:335–75. https://doi.org/10.1016/j.preteyeres.2010.03.004.

    Article  PubMed  CAS  Google Scholar 

  9. Kalatzis V, Hamel CP, MacDonald IM. Symposium obotFICR. Choroideremia: towards a therapy. Am J Ophthalmol. 2013;156:433 e3-437 e3. https://doi.org/10.1016/j.ajo.2013.05.009.

    Article  Google Scholar 

  10. Freund PR, Sergeev YV, MacDonald IM. Analysis of a large choroideremia dataset does not suggest a preference for inclusion of certain genotypes in future trials of gene therapy. Mol Genet Genomic Med. 2016;4:344–58. https://doi.org/10.1002/mgg3.208.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Roberts MF, Fishman GA, Roberts DK, Heckenlively JR, Weleber RG, Anderson RJ, et al. Retrospective, longitudinal, and cross sectional study of visual acuity impairment in choroideraemia. Br J Ophthalmol. 2002;86:658–62. https://doi.org/10.1136/bjo.86.6.658.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Freund PR, MacDonald IM. Molecular genetics of choroideremia. eLS. Chichester: Wiley; 2012.

    Google Scholar 

  13. Mura M, Sereda C, Jablonski MM, MacDonald IM, Iannaccone A. Clinical and functional findings in choroideremia due to complete deletion of the CHM gene. Arch Ophthalmol. 2007;125:1107–13. https://doi.org/10.1001/archopht.125.8.1107.

    Article  PubMed  CAS  Google Scholar 

  14. Nabholz N, Lorenzini MC, Bocquet B, Lacroux A, Faugere V, Roux AF, et al. Clinical evaluation and cone alterations in choroideremia. Ophthalmology. 2016;123:1830–2. https://doi.org/10.1016/j.ophtha.2016.02.025.

    Article  PubMed  Google Scholar 

  15. Jacobson SG, Cideciyan AV, Sumaroka A, Aleman TS, Schwartz SB, Windsor EA, et al. Remodeling of the human retina in choroideremia: rab escort protein 1 (REP-1) mutations. Invest Ophthalmol Vis Sci. 2006;47:4113–20. https://doi.org/10.1167/iovs.06-0424.

    Article  PubMed  Google Scholar 

  16. Potter MJ, Wong E, Szabo SM, McTaggart KE. Clinical findings in a carrier of a new mutation in the choroideremia gene. Ophthalmology. 2004;111:1905–9. https://doi.org/10.1016/j.ophtha.2004.04.028.

    Article  PubMed  Google Scholar 

  17. Cremers FP, van de Pol DJ, van Kerkhoff LP, Wieringa B, Ropers HH. Cloning of a gene that is rearranged in patients with choroideraemia. Nature. 1990;347:674–7. https://doi.org/10.1038/347674a0.

    Article  PubMed  CAS  Google Scholar 

  18. van Bokhoven H, van den Hurk JA, Bogerd L, Philippe C, Gilgenkrantz S, de Jong P, et al. Cloning and characterization of the human choroideremia gene. Hum Mol Genet. 1994;3:1041–6.

    Article  PubMed  Google Scholar 

  19. Stone EM, Andorf JL, Whitmore SS, DeLuca AP, Giacalone JC, Streb LM, et al. Clinically focused molecular investigation of 1000 consecutive families with inherited retinal disease. Ophthalmology. 2017;124:1314–31. https://doi.org/10.1016/j.ophtha.2017.04.008.

    Article  PubMed  Google Scholar 

  20. Radziwon A, Arno G, Wheaton DK, McDonagh EM, Baple EL, Webb-Jones K, et al. Single-base substitutions in the CHM promoter as a cause of choroideremia. Hum Mutat. 2017;38:704–15. https://doi.org/10.1002/humu.23212.

    Article  PubMed  CAS  Google Scholar 

  21. Vache C, Torriano S, Faugere V, Erkilic N, Baux D, Garcia-Garcia G, et al. Pathogenicity of novel atypical variants leading to choroideremia as determined by functional analyses. Hum Mutat. 2019;40:31–5. https://doi.org/10.1002/humu.23671.

    Article  PubMed  CAS  Google Scholar 

  22. van den Hurk JA, van de Pol DJ, Wissinger B, van Driel MA, Hoefsloot LH, de Wijs IJ, et al. Novel types of mutation in the choroideremia (CHM) gene: a full-length L1 insertion and an intronic mutation activating a cryptic exon. Hum Genet. 2003;113:268–75. https://doi.org/10.1007/s00439-003-0970-0.

    Article  PubMed  CAS  Google Scholar 

  23. Carss KJ, Arno G, Erwood M, Stephens J, Sanchis-Juan A, Hull S, et al. Comprehensive rare variant analysis via whole-genome sequencing to determine the molecular pathology of inherited retinal disease. Am J Hum Genet. 2017;100:75–90. https://doi.org/10.1016/j.ajhg.2016.12.003.

    Article  PubMed  CAS  Google Scholar 

  24. Zeitz C, Nassisi M, Laurent-Coriat C, Andrieu C, Boyard F, Condroyer C, et al. CHM mutation spectrum and disease: an update at the time of human therapeutic trials. Hum Mutat. 2021;42:323–41. https://doi.org/10.1002/humu.24174.

    Article  PubMed  CAS  Google Scholar 

  25. Dimopoulos IS, Radziwon A, St Laurent CD, MacDonald IM. Choroideremia. Curr Opin Ophthalmol. 2017;28:410–5. https://doi.org/10.1097/ICU.0000000000000392.

    Article  PubMed  Google Scholar 

  26. Sergeev YV, Smaoui N, Sui R, Stiles D, Gordiyenko N, Strunnikova N, et al. The functional effect of pathogenic mutations in Rab escort protein 1. Mutat Res. 2009;665:44–50. https://doi.org/10.1016/j.mrfmmm.2009.02.015.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Esposito G, De Falco F, Tinto N, Testa F, Vitagliano L, Tandurella IC, et al. Comprehensive mutation analysis (20 families) of the choroideremia gene reveals a missense variant that prevents the binding of REP1 with Rab geranylgeranyl transferase. Hum Mutat. 2011;32:1460–9. https://doi.org/10.1002/humu.21591.

    Article  PubMed  CAS  Google Scholar 

  28. Torriano S, Erkilic N, Faugere V, Damodar K, Hamel CP, Roux AF, et al. Pathogenicity of a novel missense variant associated with choroideremia and its impact on gene replacement therapy. Hum Mol Genet. 2017;26:3573–84. https://doi.org/10.1093/hmg/ddx244.

    Article  PubMed  CAS  Google Scholar 

  29. Sanchez-Alcudia R, Garcia-Hoyos M, Lopez-Martinez MA, Sanchez-Bolivar N, Zurita O, Gimenez A, et al. A Comprehensive analysis of choroideremia: from genetic characterization to clinical practice. PLoS ONE. 2016;11: e0151943. https://doi.org/10.1371/journal.pone.0151943.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Simunovic MP, Jolly JK, Xue K, Edwards TL, Groppe M, Downes SM, et al. The spectrum of CHM gene mutations in choroideremia and their relationship to clinical phenotype. Invest Ophthalmol Vis Sci. 2016;57:6033–9. https://doi.org/10.1167/iovs.16-20230.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Fry LE, Patricio MI, Williams J, Aylward JW, Hewitt H, Clouston P, et al. Association of messenger RNA level with phenotype in patients with choroideremia: potential implications for gene therapy dose. JAMA Ophthalmol. 2019;139:319–28. https://doi.org/10.1001/jamaophthalmol.2019.5071.

    Article  Google Scholar 

  32. Hutagalung AH, Novick PJ. Role of Rab GTPases in membrane traffic and cell physiology. Physiol Rev. 2011;91:119–49. https://doi.org/10.1152/physrev.00059.2009.

    Article  PubMed  CAS  Google Scholar 

  33. Seabra MC, Mules EH, Hume AN. Rab GTPases, intracellular traffic and disease. Trends Mol Med. 2002;8:23–30.

    Article  CAS  PubMed  Google Scholar 

  34. Pereira-Leal JB, Hume AN, Seabra MC. Prenylation of Rab GTPases: molecular mechanisms and involvement in genetic disease. FEBS Lett. 2001;498:197–200. https://doi.org/10.1016/s0014-5793(01)02483-8.

    Article  PubMed  CAS  Google Scholar 

  35. Alexandrov K, Horiuchi H, Steele-Mortimer O, Seabra MC, Zerial M. Rab escort protein-1 is a multifunctional protein that accompanies newly prenylated rab proteins to their target membranes. EMBO J. 1994;13:5262–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Alory C, Balch WE. Organization of the Rab-GDI/CHM superfamily: the functional basis for choroideremia disease. Traffic. 2001;2:532–43.

    Article  CAS  PubMed  Google Scholar 

  37. Andres DA, Seabra MC, Brown MS, Armstrong SA, Smeland TE, Cremers FP, et al. cDNA cloning of component A of Rab geranylgeranyl transferase and demonstration of its role as a Rab escort protein. Cell. 1993;73:1091–9.

    Article  CAS  PubMed  Google Scholar 

  38. Seabra MC, Brown MS, Goldstein JL. Retinal degeneration in choroideremia: deficiency of rab geranylgeranyl transferase. Science. 1993;259:377–81.

    Article  CAS  PubMed  Google Scholar 

  39. Seabra MC, Brown MS, Slaughter CA, Sudhof TC, Goldstein JL. Purification of component A of Rab geranylgeranyl transferase: possible identity with the choroideremia gene product. Cell. 1992;70:1049–57.

    Article  CAS  PubMed  Google Scholar 

  40. Cremers FP, Molloy CM, van de Pol DJ, van den Hurk JA, Bach I, Geurts van Kessel AH, et al. An autosomal homologue of the choroideremia gene colocalizes with the Usher syndrome type II locus on the distal part of chromosome 1q. Hum Mol Genet. 1992;1:71–5.

    Article  CAS  PubMed  Google Scholar 

  41. Seabra MC, Ho YK, Anant JS. Deficient geranylgeranylation of Ram/Rab27 in choroideremia. J Biol Chem. 1995;270:24420–7.

    Article  CAS  PubMed  Google Scholar 

  42. Larijani B, Hume AN, Tarafder AK, Seabra MC. Multiple factors contribute to inefficient prenylation of Rab27a in Rab prenylation diseases. J Biol Chem. 2003;278:46798–804. https://doi.org/10.1074/jbc.M307799200.

    Article  PubMed  CAS  Google Scholar 

  43. Rak A, Pylypenko O, Niculae A, Pyatkov K, Goody RS, Alexandrov K. Structure of the Rab7:REP-1 complex: insights into the mechanism of Rab prenylation and choroideremia disease. Cell. 2004;117:749–60. https://doi.org/10.1016/j.cell.2004.05.017.

    Article  PubMed  CAS  Google Scholar 

  44. Kohnke M, Delon C, Hastie ML, Nguyen UT, Wu YW, Waldmann H, et al. Rab GTPase prenylation hierarchy and its potential role in choroideremia disease. PLoS ONE. 2013;8: e81758. https://doi.org/10.1371/journal.pone.0081758.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Starr CJ, Kappler JA, Chan DK, Kollmar R, Hudspeth AJ. Mutation of the zebrafish choroideremia gene encoding Rab escort protein 1 devastates hair cells. Proc Natl Acad Sci USA. 2004;101:2572–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Moosajee M, Tulloch M, Baron RA, Gregory-Evans CY, Pereira-Leal JB, Seabra MC. Single choroideremia gene in nonmammalian vertebrates explains early embryonic lethality of the zebrafish model of choroideremia. Invest Ophthalmol Vis Sci. 2009;50:3009–16. https://doi.org/10.1167/iovs.08-2755.

    Article  PubMed  Google Scholar 

  47. Krock BL, Bilotta J, Perkins BD. Noncell-autonomous photoreceptor degeneration in a zebrafish model of choroideremia. Proc Natl Acad Sci USA. 2007;104:4600–5. https://doi.org/10.1073/pnas.0605818104.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Kossack ME, Draper BW. Genetic regulation of sex determination and maintenance in zebrafish (Danio rerio). Curr Top Dev Biol. 2019;134:119–49. https://doi.org/10.1016/bs.ctdb.2019.02.004.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. van den Hurk JA, Hendriks W, van de Pol DJ, Oerlemans F, Jaissle G, Ruther K, et al. Mouse choroideremia gene mutation causes photoreceptor cell degeneration and is not transmitted through the female germline. Hum Mol Genet. 1997;6:851–8.

    Article  PubMed  Google Scholar 

  50. Shi W, van den Hurk JA, Alamo-Bethencourt V, Mayer W, Winkens HJ, Ropers HH, et al. Choroideremia gene product affects trophoblast development and vascularization in mouse extra-embryonic tissues. Dev Biol. 2004;272:53–65. https://doi.org/10.1016/j.ydbio.2004.04.016.

    Article  PubMed  CAS  Google Scholar 

  51. Tolmachova T, Anders R, Abrink M, Bugeon L, Dallman MJ, Futter CE, et al. Independent degeneration of photoreceptors and retinal pigment epithelium in conditional knockout mouse models of choroideremia. J Clin Invest. 2006;116:386–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Tolmachova T, Wavre-Shapton ST, Barnard AR, MacLaren RE, Futter CE, Seabra MC. Retinal pigment epithelium defects accelerate photoreceptor degeneration in cell type-specific knockout mouse models of choroideremia. Invest Ophthalmol Vis Sci. 2010;51:4913–20. https://doi.org/10.1167/iovs.09-4892.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Sanjurjo-Soriano C, Kalatzis V. Guiding lights in genome editing for inherited retinal disorders: implications for gene and cell therapy. Neural Plast. 2018;2018:5056279. https://doi.org/10.1155/2018/5056279.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Han RC, Fry LE, Kantor A, McClements ME, Xue K, MacLaren RE. Is subretinal AAV gene replacement still the only viable treatment option for choroideremia? Expert Opin Orphan Drugs. 2021;9:13–24. https://doi.org/10.1080/21678707.2021.1882300.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Gerard X, Garanto A, Rozet JM, Collin RW. Antisense oligonucleotide therapy for inherited retinal dystrophies. Adv Exp Med Biol. 2016;854:517–24. https://doi.org/10.1007/978-3-319-17121-0_69.

    Article  PubMed  CAS  Google Scholar 

  56. den Hollander AI, Koenekoop RK, Yzer S, Lopez I, Arends ML, Voesenek KE, et al. Mutations in the CEP290 (NPHP6) gene are a frequent cause of Leber congenital amaurosis. Am J Hum Genet. 2006;79:556–61. https://doi.org/10.1086/507318.

    Article  Google Scholar 

  57. Collin RW, den Hollander AI, van der Velde-Visser SD, Bennicelli J, Bennett J, Cremers FP. Antisense oligonucleotide (AON)-based therapy for Leber congenital amaurosis caused by a frequent mutation in CEP290. Mol Ther Nucleic Acids. 2012;1: e14. https://doi.org/10.1038/mtna.2012.3.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Gerard X, Perrault I, Hanein S, Silva E, Bigot K, Defoort-Delhemmes S, et al. AON-mediated exon skipping restores ciliation in fibroblasts harboring the common Leber congenital amaurosis CEP290 mutation. Mol Ther Nucleic Acids. 2012;1: e29. https://doi.org/10.1038/mtna.2012.21.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Dulla K, Aguila M, Lane A, Jovanovic K, Parfitt DA, Schulkens I, et al. Splice-modulating oligonucleotide QR-110 restores CEP290 mRNA and function in human c.2991+1655A>G LCA10 models. Mol Ther Nucleic Acids. 2018;12:730–40. https://doi.org/10.1016/j.omtn.2018.07.010.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Cideciyan AV, Jacobson SG, Drack AV, Ho AC, Charng J, Garafalo AV, et al. Effect of an intravitreal antisense oligonucleotide on vision in Leber congenital amaurosis due to a photoreceptor cilium defect. Nat Med. 2019;25:225–8. https://doi.org/10.1038/s41591-018-0295-0.

    Article  PubMed  CAS  Google Scholar 

  61. Garanto A, van der Velde-Visser SD, Cremers FPM, Collin RWJ. Antisense oligonucleotide-based splice correction of a deep-intronic mutation in CHM underlying choroideremia. Adv Exp Med Biol. 2018;1074:83–9. https://doi.org/10.1007/978-3-319-75402-4_11.

    Article  PubMed  CAS  Google Scholar 

  62. Slijkerman RW, Vache C, Dona M, Garcia-Garcia G, Claustres M, Hetterschijt L, et al. Antisense oligonucleotide-based splice correction for USH2A-associated retinal degeneration caused by a frequent deep-intronic mutation. Mol Ther Nucleic Acids. 2016;5: e381. https://doi.org/10.1038/mtna.2016.89.

    Article  PubMed  CAS  Google Scholar 

  63. Garanto A, Duijkers L, Tomkiewicz TZ, Collin RWJ. Antisense oligonucleotide screening to optimize the rescue of the splicing defect caused by the recurrent deep-intronic ABCA4 variant c.4539+2001G>A in Stargardt disease. Genes (Basel). 2019. https://doi.org/10.3390/genes10060452.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Naessens S, Ruysschaert L, Lefever S, Coppieters F, De Baere E. Antisense oligonucleotide-based downregulation of the G56R pathogenic variant causing NR2E3-associated autosomal dominant retinitis pigmentosa. Genes (Basel). 2019. https://doi.org/10.3390/genes10050363.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Moosajee M, Ramsden SC, Black GC, Seabra MC, Webster AR. Clinical utility gene card for: choroideremia. Eur J Hum Genet. 2014. https://doi.org/10.1038/ejhg.2013.183.

    Article  PubMed  Google Scholar 

  66. Richardson R, Smart M, Tracey-White D, Webster AR, Moosajee M. Mechanism and evidence of nonsense suppression therapy for genetic eye disorders. Exp Eye Res. 2017;155:24–37. https://doi.org/10.1016/j.exer.2017.01.001.

    Article  PubMed  CAS  Google Scholar 

  67. Davies J, Gorini L, Davis BD. Misreading of RNA codewords induced by aminoglycoside antibiotics. Mol Pharmacol. 1965;1:93–106.

    PubMed  CAS  Google Scholar 

  68. Moosajee M, Gregory-Evans K, Ellis CD, Seabra MC, Gregory-Evans CY. 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. 2008;17:3987–4000. https://doi.org/10.1093/hmg/ddn302.

    Article  PubMed  CAS  Google Scholar 

  69. Moosajee M, Tracey-White D, Smart M, Weetall M, Torriano S, Kalatzis V, et al. 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. 2016;25:3416–31. https://doi.org/10.1093/hmg/ddw184.

    Article  PubMed  CAS  Google Scholar 

  70. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131:861–72.

    Article  CAS  PubMed  Google Scholar 

  71. Torriano S, Erkilic N, Baux D, Cereso N, De Luca V, Meunier I, et al. The effect of PTC124 on choroideremia fibroblasts and iPSC-derived RPE raises considerations for therapy. Sci Rep. 2018;8:8234. https://doi.org/10.1038/s41598-018-26481-7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Cereso N, Pequignot MO, Robert L, Becker F, De Luca V, Nabholz N, et al. Proof of concept for AAV2/5-mediated gene therapy in iPSc-derived retinal pigment epithelium of choroideremia patients. Mol Ther Methods Clin Dev. 2014;1:14011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Erkilic N, Gatinois V, Torriano S, Bouret P, Sanjurjo-Soriano C, Luca V, et al. A novel chromosomal translocation identified due to complex genetic instability in iPSC generated for choroideremia. Cells. 2019. https://doi.org/10.3390/cells8091068.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Keeling KM, Wang D, Conard SE, Bedwell DM. Suppression of premature termination codons as a therapeutic approach. Crit Rev Biochem Mol Biol. 2012;47:444–63. https://doi.org/10.3109/10409238.2012.694846.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Sarkar H, Mitsios A, Smart M, Skinner J, Welch AA, Kalatzis V, et al. Nonsense-mediated mRNA decay efficiency varies in choroideremia providing a target to boost small molecule therapeutics. Hum Mol Genet. 2019;28:1865–71. https://doi.org/10.1093/hmg/ddz028.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Trapani I, Puppo A, Auricchio A. Vector platforms for gene therapy of inherited retinopathies. Prog Retin Eye Res. 2014;43:108–28. https://doi.org/10.1016/j.preteyeres.2014.08.001.

    Article  PubMed  CAS  Google Scholar 

  77. Tolmachova T, Tolmachov OE, Barnard AR, de Silva SR, Lipinski DM, Walker NJ, et al. Functional expression of Rab escort protein 1 following AAV2-mediated gene delivery in the retina of choroideremia mice and human cells ex vivo. J Mol Med (Berl). 2013;91:825–37. https://doi.org/10.1007/s00109-013-1006-4.

    Article  CAS  Google Scholar 

  78. Lotery AJ, Yang GS, Mullins RF, Russell SR, Schmidt M, Stone EM, et al. Adeno-associated virus type 5: transduction efficiency and cell-type specificity in the primate retina. Hum Gene Ther. 2003;14:1663–71.

    Article  CAS  PubMed  Google Scholar 

  79. Allocca M, Mussolino C, Garcia-Hoyos M, Sanges D, Iodice C, Petrillo M, et al. Novel adeno-associated virus serotypes efficiently transduce murine photoreceptors. J Virol. 2007;81:11372–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Black A, Vasireddy V, Chung DC, Maguire AM, Gaddameedi R, Tolmachova T, et al. Adeno-associated virus 8-mediated gene therapy for choroideremia: preclinical studies in in vitro and in vivo models. J Gene Med. 2014;16:122–30. https://doi.org/10.1002/jgm.2768.

    Article  PubMed  CAS  Google Scholar 

  81. Duong TT, Vasireddy V, Ramachandran P, Herrera PS, Leo L, Merkel C, et al. Use of induced pluripotent stem cell models to probe the pathogenesis of choroideremia and to develop a potential treatment. Stem Cell Res. 2018;27:140–50. https://doi.org/10.1016/j.scr.2018.01.009.

    Article  PubMed  CAS  Google Scholar 

  82. Yamaoka M, Ando T, Terabayashi T, Okamoto M, Takei M, Nishioka T, et al. PI3K regulates endocytosis after insulin secretion by mediating signaling crosstalk between Arf6 and Rab27a. J Cell Sci. 2016;129:637–49. https://doi.org/10.1242/jcs.180141.

    Article  PubMed  CAS  Google Scholar 

  83. Trapani I, Auricchio A. Has retinal gene therapy come of age? From bench to bedside and back to bench. Hum Mol Genet. 2019;28:R108–18. https://doi.org/10.1093/hmg/ddz130.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Marlhens F, Bareil C, Griffoin J-M, Zrenner E, Amalric P, Eliaou C, et al. Mutations in RPE65 cause Leber’s congenital amaurosis. Nat Genet. 1997;17:139–41.

    Article  CAS  PubMed  Google Scholar 

  85. Moiseyev G, Chen Y, Takahashi Y, Wu BX, Ma JX. RPE65 is the isomerohydrolase in the retinoid visual cycle. Proc Natl Acad Sci USA. 2005;102:12413–8. https://doi.org/10.1073/pnas.0503460102.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Acland GM, Aguirre GD, Ray J, Zhang Q, Aleman TS, Cideciyan AV, et al. Gene therapy restores vision in a canine model of childhood blindness. Nat Genet. 2001;28:92–5.

    PubMed  CAS  Google Scholar 

  87. Acland GM, Aguirre GD, Bennett J, Aleman TS, Cideciyan AV, Bennicelli 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;12:1072–82. https://doi.org/10.1016/j.ymthe.2005.08.008.

    Article  PubMed  CAS  Google Scholar 

  88. Maguire AM, High KA, Auricchio A, Wright JF, Pierce EA, Testa F, et al. Age-dependent effects of RPE65 gene therapy for Leber’s congenital amaurosis: a phase 1 dose-escalation trial. Lancet. 2009;374:1597–605. https://doi.org/10.1016/S0140-6736(09)61836-5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Maguire AM, Simonelli F, Pierce EA, Pugh EN Jr, Mingozzi F, Bennicelli J, et al. Safety and efficacy of gene transfer for Leber’s congenital amaurosis. N Engl J Med. 2008;358:2240–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Bennett J, Ashtari M, Wellman J, Marshall KA, Cyckowski LL, Chung DC, et al. AAV2 gene therapy readministration in three adults with congenital blindness. Sci Transl Med. 2012;4:120ra15. https://doi.org/10.1126/scitranslmed.3002865.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Bennett J, Wellman J, Marshall KA, McCague S, Ashtari M, DiStefano-Pappas 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. https://doi.org/10.1016/S0140-6736(16)30371-3.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Russell S, Bennett J, Wellman JA, Chung DC, Yu ZF, Tillman A, 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;390:849–60. https://doi.org/10.1016/S0140-6736(17)31868-8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. MacLaren RE, Groppe M, Barnard AR, Cottriall CL, Tolmachova T, Seymour L, et al. Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial. Lancet. 2014;383:1129–37. https://doi.org/10.1016/S0140-6736(13)62117-0.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Edwards TL, Jolly JK, Groppe M, Barnard AR, Cottriall CL, Tolmachova T, et al. Visual acuity after retinal gene therapy for choroideremia. N Engl J Med. 2016;374:1996–8. https://doi.org/10.1056/NEJMc1509501.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Xue K, Jolly JK, Barnard AR, Rudenko A, Salvetti AP, Patricio MI, et al. Beneficial effects on vision in patients undergoing retinal gene therapy for choroideremia. Nat Med. 2018;24:1507–12. https://doi.org/10.1038/s41591-018-0185-5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Dimopoulos IS, Hoang SC, Radziwon A, Binczyk NM, Seabra MC, MacLaren RE, et al. Two-year results after AAV2-mediated gene therapy for choroideremia: the Alberta experience. Am J Ophthalmol. 2018;193:130–42. https://doi.org/10.1016/j.ajo.2018.06.011.

    Article  PubMed  Google Scholar 

  97. Lam BL, Davis JL, Gregori NZ, MacLaren RE, Girach A, Verriotto JD, et al. Choroideremia gene therapy phase 2 clinical trial: 24-month results. Am J Ophthalmol. 2019;197:65–73. https://doi.org/10.1016/j.ajo.2018.09.012.

    Article  PubMed  CAS  Google Scholar 

  98. Fischer MD, Ochakovski GA, Beier B, Seitz IP, Vaheb Y, Kortuem C, et al. Efficacy and safety of retinal gene therapy using adeno-associated virus vector for patients with choroideremia: a randomized clinical trial. JAMA Ophthalmol. 2019;137:1247–54. https://doi.org/10.1001/jamaophthalmol.2019.3278.

    Article  PubMed  PubMed Central  Google Scholar 

  99. Vasireddy V, Mills JA, Gaddameedi R, Basner-Tschakarjan E, Kohnke M, Black AD, et al. AAV-mediated gene therapy for choroideremia: preclinical studies in personalized models. PLoS ONE. 2013;8: e61396. https://doi.org/10.1371/journal.pone.0061396.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Ross M, Ofri R. The future of retinal gene therapy: evolving from subretinal to intravitreal vector delivery. Neural Regen Res. 2021;16:1751–9. https://doi.org/10.4103/1673-5374.306063.

    Article  PubMed  PubMed Central  Google Scholar 

  101. Kotterman MA, Schaffer DV. Engineering adeno-associated viruses for clinical gene therapy. Nat Rev Genet. 2014;15:445–51. https://doi.org/10.1038/nrg3742.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Dalkara D, Byrne LC, Klimczak RR, Visel M, Yin L, Merigan WH, et al. In vivo-directed evolution of a new adeno-associated virus for therapeutic outer retinal gene delivery from the vitreous. Sci Transl Med. 2013;5:189ra76. https://doi.org/10.1126/scitranslmed.3005708.

    Article  PubMed  CAS  Google Scholar 

  103. Ramachandran PS, Lee V, Wei Z, Song JY, Casal G, Cronin T, et al. Evaluation of dose and safety of AAV7m8 and AAV8BP2 in the non-human primate retina. Hum Gene Ther. 2017;28:154–67. https://doi.org/10.1089/hum.2016.111.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Byrne LC, Day TP, Visel M, Strazzeri JA, Fortuny C, Dalkara D, et al. In vivo-directed evolution of adeno-associated virus in the primate retina. JCI Insight. 2020. https://doi.org/10.1172/jci.insight.135112.

    Article  PubMed  PubMed Central  Google Scholar 

  105. Bruewer AR, Mowat FM, Bartoe JT, Boye SL, Hauswirth WW, Petersen-Jones SM. Evaluation of lateral spread of transgene expression following subretinal AAV-mediated gene delivery in dogs. PLoS ONE. 2013;8: e60218. https://doi.org/10.1371/journal.pone.0060218.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Bordet T, Behar-Cohen F. Ocular gene therapies in clinical practice: viral vectors and nonviral alternatives. Drug Discov Today. 2019;24:1685–93. https://doi.org/10.1016/j.drudis.2019.05.038.

    Article  PubMed  CAS  Google Scholar 

  107. Adijanto J, Naash MI. Nanoparticle-based technologies for retinal gene therapy. Eur J Pharm Biopharm. 2015;95:353–67. https://doi.org/10.1016/j.ejpb.2014.12.028.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Kelley RA, Conley SM, Makkia R, Watson JN, Han Z, Cooper MJ, et al. DNA nanoparticles are safe and nontoxic in non-human primate eyes. Int J Nanomed. 2018;13:1361–79. https://doi.org/10.2147/IJN.S157000.

    Article  CAS  Google Scholar 

  109. Cideciyan AV, Jacobson SG, Beltran WA, Sumaroka A, Swider M, Iwabe S, et al. Human retinal gene therapy for Leber congenital amaurosis shows advancing retinal degeneration despite enduring visual improvement. Proc Natl Acad Sci USA. 2013;110:E517–25. https://doi.org/10.1073/pnas.1218933110.

    Article  PubMed  PubMed Central  Google Scholar 

  110. Hippert C, Dubois G, Morin C, Disson O, Ibanes S, Jacquet C, et al. Gene transfer may be preventive but not curative for a lysosomal transport disorder. Mol Ther. 2008;16:1372–81.

    Article  CAS  PubMed  Google Scholar 

  111. Petit L, Khanna H, Punzo C. Advances in gene therapy for diseases of the eye. Hum Gene Ther. 2016;27:563–79. https://doi.org/10.1089/hum.2016.040.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  112. Dimopoulos IS, Chan S, MacLaren RE, MacDonald IM. Pathogenic mechanisms and the prospect of gene therapy for choroideremia. Expert Opin Orphan Drugs. 2015;3:787–98. https://doi.org/10.1517/21678707.2015.1046434.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Kondkar AA, Abu-Amero KK. Leber congenital amaurosis: current genetic basis, scope for genetic testing and personalized medicine. Exp Eye Res. 2019;189: 107834. https://doi.org/10.1016/j.exer.2019.107834.

    Article  PubMed  CAS  Google Scholar 

  114. Jayasundera KT, Abuzaitoun RO, Lacy GD, Abalem MF, Saltzman GM, Ciulla TA, et al. Challenges of cost-effectiveness analyses of novel therapeutics for inherited retinal diseases: cost-effectiveness analysis in inherited retinal diseases. Am J Ophthalmol. 2021. https://doi.org/10.1016/j.ajo.2021.08.009.

    Article  PubMed  Google Scholar 

  115. Garafalo AV, Cideciyan AV, Heon E, Sheplock R, Pearson A, WeiYang YuC, et al. Progress in treating inherited retinal diseases: early subretinal gene therapy clinical trials and candidates for future initiatives. Prog Retin Eye Res. 2020;77: 100827. https://doi.org/10.1016/j.preteyeres.2019.100827.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We thank David Baux for sharing data from the LOVD-CHM database. We also thank Carla Sanjurjo-Soriano, Simona Torriano and Daria Mamaeva for critical reading of the manuscript. This work was supported by Inserm, CHU Montpellier, and the University of Montpellier.

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  1. Institute for Neurosciences of Montpellier, Univ Montpellier, Inserm U1298, Hôpital St Eloi, 80 Avenue Augustin Fliche, 34091, Montpellier, France

    Vasiliki Kalatzis, Anne-Françoise Roux & Isabelle Meunier

  2. Molecular Genetics Laboratory, Univ Montpellier, CHU Montpellier, Montpellier, France

    Anne-Françoise Roux

  3. National Reference Centre for Inherited Sensory Diseases, University of Montpellier, CHU Montpellier, Montpellier, France

    Isabelle Meunier

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  1. Vasiliki Kalatzis
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Correspondence to Vasiliki Kalatzis.

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A-FR and IM have no conflicts of interest to declare. VK is scientific co-founder and consultant of Horama.

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VK performed the literature search and wrote the first draft of the manuscript. VK, A-FR and IM analysed data, prepared figures and critically reviewed the manuscript.

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Kalatzis, V., Roux, AF. & Meunier, I. Molecular Therapy for Choroideremia: Pre-clinical and Clinical Progress to Date. Mol Diagn Ther 25, 661–675 (2021). https://doi.org/10.1007/s40291-021-00558-y

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