158
Views
2
CrossRef citations to date
0
Altmetric
Invited Review

Translational readthrough inducing drugs for the treatment of inherited retinal dystrophies

, &
Pages 169-182 | Received 22 Aug 2019, Accepted 27 Apr 2020, Published online: 08 Jun 2020

References

  • Liew G, Michaelides M, Bunce C. A comparison of the causes of blindness certifications in England and Wales in working age adults (16-64 years), 1999-2000 with 2009-2010. BMJ Open. 2014;4(2):e004015.
  • Frick KD, Roebuck MC, Feldstein JI, et al. Health services utilization and cost of retinitis pigmentosa. Arch Ophthalmol. 2012;130(5):629–634. Chicago, Ill. 1960.
  • Hamblion EL, Moore AT, Rahi JS. The health-related quality of life of children with hereditary retinal disorders and the psychosocial impact on their families. Investig Ophthalmol Vis Sci. 2011;52(11):7981–7986.
  • Pierce EA, Bennett J. The status of RPE65 gene therapy trials: safety and efficacy. Cold Spring Harb Perspect Med. 2015;5(9):a017285–a017285.
  • Cideciyan AV, Jacobson SG, Beltran WA, et al. Human retinal gene therapy for leber congenital amaurosis shows advancing retinal degeneration despite enduring visual improvement. Proc Natl Acad Sci. 2013;110(6):E517–E525.
  • MacLaren RE, Groppe M, Barnard AR, et al. Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial. Lancet. 2014;383(9923):1129–1137.
  • Petit L, Khanna H, Punzo C. Advances in gene therapy for diseases of the eye. Hum Gene Ther. 2016;27(8):563–579.
  • Dias N, Stein CA. Antisense oligonucleotides: basic concepts and mechanisms. Mol Cancer Ther. 2002;1(5):347–355.
  • Dulla K, Aguila M, Lane A, 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;12:730–740.
  • Slijkerman RW, Vaché C, Dona M, 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.
  • Collin RW, den Hollander AI, van der Velde-visser SD, et al. Antisense oligonucleotide (AON)-based therapy for leber congenital amaurosis caused by a frequent mutation in CEP290. Mol Ther Nucleic Acids. 2012;1:e14.
  • Zanardi TA, Kim T-W, Shen L, et al. Chronic toxicity assessment of 2′--methoxyethyl antisense oligonucleotides in mice. Nucleic Acid Ther. 2018;28(4):233–241.
  • Mort M, Ivanov D, Cooper DN, et al. A meta-analysis of nonsense mutations causing human genetic disease. Hum Mutat. 2008;29(8):1037–1047.
  • Richardson R, Hingorani M, Van Heyningen V, et al. Clinical utility gene card for: aniridia. Eur J Hum Genet. 2016;24(11):4.
  • Moosajee M, Ramsden SC, Black GC, et al. Clinical utility gene card for: choroideremia. Eur J Hum Genet. 2014;22(4):572.
  • Mendell JT, Dietz HC. When the message goes awry: disease-producing mutations that influence mRNA content and performance. Cell. 2001;107(4):411–414.
  • Lewis BP, Green RE, Brenner SE. Evidence for the widespread coupling of alternative splicing and nonsense-mediated mRNA decay in humans. Proc Natl Acad Sci. 2003;100(1):189–192.
  • Pan Q, Saltzman AL, Kim YK, et al. Quantitative microarray profiling provides evidence against widespread coupling of alternative splicing with nonsense-mediated mRNA decay to control gene expression. Genes Dev. 2006;20(2):153–158.
  • Bidou L, Allamand V, Rousset J-P, et al. Sense from nonsense: therapies for premature stop codon diseases. Trends Mol Med. 2012;18(11):679–688.
  • Inoue K, Khajavi M, Ohyama T, et al. Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations. Nat Genet. 2004;36(4):361–369.
  • Manuvakhova M, Keeling K, DM B. Aminoglycoside antibiotics mediate context-dependent suppression of termination codons in a mammalian translation system. RNA. 2000;6(7):1044–1055.
  • Kervestin S, Jacobson A. NMD: a multifaceted response to premature translational termination. Nat Rev Mol Cell Biol. 2012;13(11):700–712.
  • Celik A, Kervestin S, Jacobson A. NMD: at the crossroads between translation termination and ribosome recycling. Biochimie. 2015;114:2–9.
  • Yamashita A, Izumi N, Kashima I, et al. SMG-8 and SMG-9, two novel subunits of the SMG-1 complex, regulate remodeling of the mRNA surveillance complex during nonsense-mediated mRNA decay. Genes Dev. 2009;23(9):1091–1105.
  • Ivanov PV, Gehring NH, Kunz JB, et al. Interactions between UPF1, eRFs, PABP and the exon junction complex suggest an integrated model for mammalian NMD pathways. Embo J. 2008;27(5):736–747.
  • He F, Jacobson A. Nonsense-mediated mRNA decay: degradation of defective transcripts is only part of the story. Annu Rev Genet. 2015;49(1):339–366.
  • Lykke-Andersen J, Di SM, Steitz JA. Human Upf proteins target an mRNA for nonsense-mediated decay when downstream of a termination codon. Cell. 2000;103(7):1121–1131.
  • He F, Li X, Spatrick P, et al. Genome-wide analysis of mRNAs regulated by the nonsense-mediated and 5′ to 3′ mRNA decay pathways in yeast. Mol Cell. 2003;12(6):1439–1452.
  • Silva AL, Ribeiro P, Inacio A, et al. Proximity of the poly(A)-binding protein to a premature termination codon inhibits mammalian nonsense-mediated mRNA decay. RNA. 2008;14(3):563–576.
  • Pereira FJC, Teixeira A, Kong J, et al. Resistance of mRNAs with AUG-proximal nonsense mutations to nonsense-mediated decay reflects variables of mRNA structure and translational activity. Nucleic Acids Res. 2015;43(13):6528–6544.
  • Barbosa C, Peixeiro I, Romão L. Gene expression regulation by upstream open reading frames and human disease. Fisher EMC, editor. PLoS Genet. 2013;9(8):e1003529.
  • Zetoune AB, Fontanière S, Magnin D, et al. Comparison of nonsense-mediated mRNA decay efficiency in various murine tissues. BMC Genet. 2008;9(1):83.
  • Linde L, Boelz S, Nissim-Rafinia M, et al. Nonsense-mediated mRNA decay affects nonsense transcript levels and governs response of cystic fibrosis patients to gentamicin. J Clin Invest. 2007;117(3):683–692.
  • Nguyen LS, Wilkinson MF, Gecz J. Nonsense-mediated mRNA decay: inter-individual variability and human disease. Neurosci Biobehav Rev. 2014;46:175–186.
  • Sarkar H, Mitsios A, Smart M, et al., Nonsense-mediated mRNA decay efficiency varies in choroideremia providing a target to boost small molecule therapeutics. Hum Mol Genet. 2019;28(11): 1865–1871.
  • Yamashita A, Ohnishi T, Kashima I, et al. Human SMG-1, a novel phosphatidylinositol 3-kinase-related protein kinase, associates with components of the mRNA surveillance complex and is involved in the regulation of nonsense-mediated mRNA decay. Genes Dev. 2001;15(17):2215–2228.
  • Usuki F, Yamashita A, Higuchi I, et al. Inhibition of nonsense-mediated mRNA decay rescues the phenotype in ullrich’s disease. Ann Neurol. 2004;55(5):740–744.
  • Durand S, Cougot N, Mahuteau-Betzer F, et al. Inhibition of nonsense-mediated mRNA decay (NMD) by a new chemical molecule reveals the dynamic of NMD factors in P-bodies. J Cell Biol. 2007;178(7):1145–1160.
  • Keeling KM, Wang D, Dai Y, et al. Attenuation of nonsense-mediated mRNA decay enhances in vivo nonsense suppression. Reiner DJ, editor. PLoS One. 2013;8(4):e60478.
  • Gotham VJB, Hobbs MC, Burgin R, et al. Synthesis and activity of a novel inhibitor of nonsense-mediated mRNA decay. Org Biomol Chem. 2016;14(5):1559–1563.
  • Atanasova VS, Jiang Q, Prisco M, et al. Amlexanox enhances premature termination codon read-through in COL7A1 and expression of full length type VII collagen: potential therapy for recessive dystrophic epidermolysis bullosa. J Invest Dermatol. 2017;137(9):1842–1849.
  • Gonzalez-Hilarion S, Beghyn T, Jia J, et al., Rescue of nonsense mutations by amlexanox in human cells. Orphanet J Rare Dis. 2012;7(1): 58.
  • Seoighe C, Gehring C. Heritability in the efficiency of nonsense-mediated mRNA decay in humans. PLoS One. 2010;5(7):e11657.
  • Rodnina MV, Gromadski KB, Kothe U, et al. Recognition and selection of tRNA in translation. FEBS Lett. 2005;579(4):938–942.
  • Keeling KM, Wang D, Conard SE, et al. Suppression of premature termination codons as a therapeutic approach. Crit Rev Biochem Mol Biol. 2012;47(5):444–463.
  • Richardson R, Smart M, Tracey-White D, et al. Mechanism and evidence of nonsense suppression therapy for genetic eye disorders. Exp Eye Res. 2017;155:24–37.
  • Dabrowski M, Bukowy-Bieryllo Z, Zietkiewicz E. Translational readthrough potential of natural termination codons in eucaryotes – the impact of RNA sequence. RNA Biol. 2015;12(9):950–958.
  • Floquet C, Hatin I, Rousset J-P, et al. Statistical analysis of readthrough levels for nonsense mutations in mammalian cells reveals a major determinant of response to gentamicin. Flanigan KM, editor. PLoS Genet. 2012;8(3):e1002608.
  • Keeling KM, Xue X, Gunn G, et al. Therapeutics based on stop codon readthrough. Annu Rev Genomics Hum Genet. 2014 April 18;15(1):371–394.
  • Howard MT, Shirts BH, Petros LM, et al. Sequence specificity of aminoglycoside-induced stop condon readthrough: potential implications for treatment of duchenne muscular dystrophy. Ann Neurol. 2000;48(2):164–169.
  • Bonetti B, Fu L, Moon J, et al. The efficiency of translation termination is determined by a synergistic interplay between upstream and downstream sequences in saccharomyces cerevisiae. J Mol Biol. 1995;251(3):334–345.
  • Tork S, Hatin I, Rousset JP, et al. The major 5′ determinant in stop codon read-through involves two adjacent adenines. Nucleic Acids Res. 2004;32(2):415–421.
  • Guerin K, Gregory-Evans CY, Hodges MD, et al., Systemic aminoglycoside treatment in rodent models of retinitis pigmentosa. Exp Eye Res. 2008;87(3): 197–207.
  • Carnes J, Jacobson M, Leinwand L, et al. Stop codon suppression via inhibition of eRF1 expression. RNA. 2003;9(6):648–653.
  • Singleton RS, Liu-Yi P, Formenti F, et al. OGFOD1 catalyzes prolyl hydroxylation of RPS23 and is involved in translation control and stress granule formation. Proc Natl Acad Sci U S A. 2014;111(11):4031–4036.
  • Loenarz C, Sekirnik R, Thalhammer A, et al. Hydroxylation of the eukaryotic ribosomal decoding center affects translational accuracy. Proc Natl Acad Sci U S A. 2014;111(11):4019–4024.
  • Moosajee M, Tracey-White D, Smart M, 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(16): 3416–3431.
  • Goldmann T, Overlack N, Möller F, et al., A comparative evaluation of NB30, NB54 and PTC124 in translational read-through efficacy for treatment of an USH1C nonsense mutation. EMBO Mol Med. 2012;4(11): 1186–1199.
  • Bordeira-Carriço R, Pêgo AP, Santos M, et al. Cancer syndromes and therapy by stop-codon readthrough. Trends Mol Med. 2012;18(11):667–678.
  • Sergeev YV, Smaoui N, Sui R, et al. The functional effect of pathogenic mutations in Rab escort protein 1. Mutat Res Mol Mech Mutagen. 2009;665(1–2):44–50.
  • Esposito G, De Falco F, Tinto N, 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(12):1460–1469.
  • Ouyang X, Xia X, Verpy E, et al. Mutations in the alternatively spliced exons of USH1C cause non-syndromic recessive deafness. Hum Genet. 2002;111(1):26–30.
  • Lima Cunha D, Arno G, Corton M, et al. The spectrum of PAX6 mutations and genotype-phenotype correlations in the eye. Genes (Basel). 2019;10(12).
  • Torriano S, Erkilic N, Baux D, et al. The effect of PTC124 on choroideremia fibroblasts and iPSC-derived RPE raises considerations for therapy. Sci Rep. 2018;8(1):8234.
  • Mingeot-Leclercq MP, Glupczynski Y, Tulkens PM. Aminoglycosides: activity and resistance. Antimicrob Agents Chemother. 1999;43(4):727–737.
  • Nagel-Wolfrum K, Möller F, Penner I, et al. Targeting nonsense mutations in diseases with translational read-through-inducing drugs (TRIDs). BioDrugs. 2016;30(2):49–74.
  • Nudelman I, Glikin D, Smolkin B, et al. Repairing faulty genes by aminoglycosides: development of new derivatives of geneticin (G418) with enhanced suppression of diseases-causing nonsense mutations. Bioorg Med Chem. 2010;18(11):3735–3746.
  • Hainrichson M, Nudelman I, Baasov T. Designer aminoglycosides: the race to develop improved antibiotics and compounds for the treatment of human genetic diseases. Org Biomol Chem. 2008;6(2):227–239.
  • Du M, Jones JR, Lanier J, et al. Aminoglycoside suppression of a premature stop mutation in a Cftr-/- mouse carrying a human CFTR-G542X transgene. J Mol Med. 2002;80(9):595–604.
  • Shoturma DI, Leland SE, Cordier L, et al. Aminoglycoside antibiotics restore dystrophin function to skeletal muscles of mdx mice. J Clin Invest. 2008;104:375–381.
  • Floquet C, Rousset J-P, Bidou L. Readthrough of premature termination codons in the adenomatous polyposis coli gene restores its biological activity in human cancer cells. Deb S, editor. PLoS One. 2011;6(8):e24125.
  • Moestrup SK, Cui S, Vorum H, et al. Evidence that epithelial glycoprotein 330/megalin mediates uptake of polybasic drugs. J Clin Invest. 1995;96(3):1404–1413.
  • Du M, Keeling KM, Fan L, et al. Poly-l-aspartic acid enhances and prolongs gentamicin-mediated suppression of the CFTR-G542X mutation in a cystic fibrosis mouse model. J Biol Chem. 2009;284(11):6885–6892.
  • Fiscella RG, Gieser J, Phillpotts B, et al. Intraocular penetration of gentamicin after once-daily aminoglycoside dosing. Retina. 1998;18(4):339–342.
  • Nudelman I, Rebibo-Sabbah A, Shallom-Shezifi D, et al., Redesign of aminoglycosides for treatment of human genetic diseases caused by premature stop mutations. Bioorg Med Chem Lett. 2006;16(24): 6310–6315.
  • Pfister P, Hobbie S, Vicens Q, et al. The molecular basis for A-site mutations conferring aminoglycoside resistance: relationship between ribosomal susceptibility and X-ray crystal structures. ChemBioChem. 2003;4(10):1078–1088.
  • Goldmann T, Rebibo-Sabbah A, Overlack N, et al., Beneficial read-through of a USH1C nonsense mutation by designed aminoglycoside NB30 in the retina. Investig Ophthalmol Vis Sci. 2010;51(12): 6671–6680.
  • Shulman E, Belakhov V, Wei G, et al. Designer aminoglycosides that selectively inhibit cytoplasmic rather than mitochondrial ribosomes show decreased ototoxicity: a strategy for the treatment of genetic diseases. J Biol Chem. 2014;289(4):2318–2330.
  • Kondo J, Hainrichson M, Nudelman I, et al. Differential selectivity of natural and synthetic aminoglycosides towards the eukaryotic and prokaryotic decoding a sites. ChemBioChem. 2007;8(14):1700–1709.
  • Nudelman I, Rebibo-Sabbah A, Cherniavsky M, et al., Development of novel aminoglycoside (NB54) with reduced toxicity and enhanced suppression of disease-causing premature stop mutations. J Med Chem. 2009;52(9): 2836–2845.
  • Xue X, Mutyam V, Tang L, et al. Synthetic aminoglycosides efficiently suppress cystic fibrosis transmembrane conductance regulator nonsense mutations and are enhanced by ivacaftor. Am J Respir Cell Mol Biol. 2014;50(4):805.
  • Leubitz A, Frydman-Marom A, Sharpe N, et al. Safety, tolerability, and pharmacokinetics of single ascending doses of ELX-02, a potential treatment for genetic disorders caused by nonsense mutations, in healthy volunteers. Clin Pharmacol Drug Dev. 2019;8(8):984–994.
  • Orphanet. 6ʹ-(R)-methyl-5-O-(5-amino-5,6-dideoxy-alpha-L-talofuranosyl)-par omamine sulfate [Internet]. Orphanet an online database rare Dis. orphan drugs. Copyright, Inser. 1997. 1997 [cited 2019 Oct 21]. Available from: https://www.orpha.net/consor/cgi-bin/Drugs_Search.php?lng=EN&data_id=3265&Substance=6—R–methyl-5-O–5-amino-5-6-dideoxy-alpha-L-talofuranosyl–paromamine-sulfate&search=Drugs_Search_SubstanceTradename&data_type=Product&diseaseType=Drug&Typ=Sub&title=&d.
  • Deubner R, Schollmayer C, Wienen F, et al. Assignment of the major and minor components of gentamicin for evaluation of batches. Magn Reson Chem. 2003;41(8):589–598.
  • Vydrin AF, Shikhaleev IV, Makhortov VL, et al. Component composition of gentamicin sulfate preparations. Pharm Chem J. 2003;37(8):448–450.
  • Stypulkowska K, Blazewicz A, Fijalek Z, et al. Determination of gentamicin sulphate composition and related substances in pharmaceutical preparations by LC with charged aerosol detection. Chromatographia. 2010;72(11–12):1225–1229.
  • Friesen WJ, Johnson B, Sierra J, et al. The minor gentamicin complex component, X2, is a potent premature stop codon readthrough molecule with therapeutic potential. PLoS One. 2018;13(10):e0206158.
  • Welch EM, Barton ER, Zhuo J, et al., PTC124 targets genetic disorders caused by nonsense mutations. Nature. 2007;447(7140): 87–91.
  • Roy B, Friesen WJ, Tomizawa Y, et al. Ataluren stimulates ribosomal selection of near-cognate tRNAs to promote nonsense suppression. Proc Natl Acad Sci U S A. 2016;113(44):12508–12513.
  • Kerem E, Konstan MW, De Boeck K, et al. Ataluren for the treatment of nonsense-mutation cystic fibrosis: a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Respir Med. 2014;2(7):539–547.
  • McDonald CM, Campbell C, Torricelli RE, et al. Ataluren in patients with nonsense mutation duchenne muscular dystrophy (ACT DMD): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;390(10101):1489–1498.
  • Gregory-Evans CY, Wang X, Wasan KM, et al., Postnatal manipulation of Pax6 dosage reverses congenital tissue malformation defects. J Clin Invest. 2014;124(1): 111–116.
  • Du L, Jung ME, Damoiseaux R, et al. A new series of small molecular weight compounds induce read through of all three types of nonsense mutations in the ATM gene. Mol Ther. 2013;21(9):1653–1660.
  • Kayali R, Ku J-M, Khitrov G, et al. Read-through compound 13 restores dystrophin expression and improves muscle function in the mdx mouse model for Duchenne muscular dystrophy. Hum Mol Genet. 2012;21(18):4007–4020.
  • Du L, Damoiseaux R, Nahas S, et al. Nonaminoglycoside compounds induce readthrough of nonsense mutations. J Exp Med. 2009;206(10):2285–2297.
  • Bell J. Amlexanox for the treatment of recurrent aphthous ulcers. Clin Drug Investig. 2005;25(9):555–566.
  • Xue K, MacLaren RE. Ocular gene therapy for choroideremia: clinical trials and future perspectives. Expert Rev Ophthalmol. 2018;13(3):129–138.
  • Aleman TS, Huckfeldt RM, Serrano L, et al. AAV2-hCHM subretinal delivery to the macula in choroideremia: 2 year results of an ongoing phase I/II gene therapy trial. Invest Ophthalmol Vis Sci. 2019;60:5173.
  • Moosajee M, Gregory-Evans K, Ellis CD, et al. 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(24):3987–4000.
  • Hamel C. Retinitis pigmentosa. Orphanet J Rare Dis. 2006;1(1):40.
  • Dryja TP, McGee TL, Hahn LB, et al. Mutations within the rhodopsin gene in patients with autosomal dominant retinitis pigmentosa. N Engl J Med. 1990;323(19):1302–1307.
  • Breuer DK, Yashar BM, Filippova E, et al. A comprehensive mutation analysis of RP2 and RPGR in a North American cohort of families with X-linked retinitis pigmentosa. Am J Hum Genet. 2002;70(6):1545–1554.
  • Branham K, Othman M, Brumm M, et al. Mutations in RPGR and RP2 account for 15% of males with simplex retinal degenerative disease. Invest Ophthalmol Vis Sci. 2012;53(13):8232–8237.
  • Hardcastle AJ, Thiselton DL, Van Maldergem L, et al. Mutations in the RP2 gene cause disease in 10% of families with familial X-linked retinitis pigmentosa assessed in this study. Am J Hum Genet. 1999;64(4):1210–1215.
  • Grayson C, Chapple JP, Willison KR, et al. In vitro analysis of aminoglycoside therapy for the Arg120stop nonsense mutation in RP2 patients. J Med Genet. 2002;39(1):62–67.
  • Schwarz N, Carr A-J, Lane A, et al., Translational read-through of the RP2 Arg120stop mutation in patient iPSC-derived retinal pigment epithelium cells. Hum Mol Genet. 2015;24(4): 972–986.
  • Ostergaard E, Duno M, Batbayli M, et al. A novel MERTK deletion is a common founder mutation in the Faroe Islands and is responsible for a high proportion of retinitis pigmentosa cases. Mol Vis. 2011;17:1485–1492.
  • Feng W, Yasumura D, Matthes MT, et al. Mertk triggers uptake of photoreceptor outer segments during phagocytosis by cultured retinal pigment epithelial cells. J Biol Chem. 2002;277(19):17016–17022.
  • Ghazi NG, Abboud EB, Nowilaty SR, 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(3):327–343.
  • Ramsden CM, Nommiste BR, Lane A, et al., Rescue of the MERTK phagocytic defect in a human iPSC disease model using translational read-through inducing drugs. Sci Rep. 2017;7(1): 51.
  • Kumaran N, Moore AT, Weleber RG, et al. Leber congenital amaurosis/early-onset severe retinal dystrophy: clinical features, molecular genetics and therapeutic interventions. Br J Ophthalmol BMJ Publishing Group. 2017;101(9):1147–1154.
  • Pattnaik BR, Shahi PK, Marino MJ, et al. A novel KCNJ13 nonsense mutation and loss of Kir7.1 channel function causes Leber Congenital Amaurosis (LCA16). Hum Mutat. 2015;36(7):720–727.
  • Sergouniotis PI, Davidson AE, Mackay DS, et al. Recessive mutations in KCNJ13, encoding an inwardly rectifying potassium channel subunit, cause leber congenital amaurosis. Am J Hum Genet. 2011;89(1):183–190.
  • Roman D, Zhong H, Yaklichkin S, et al. Conditional loss of Kcnj13 in the retinal pigment epithelium causes photoreceptor degeneration. Exp Eye Res. 2018;176:219–226.
  • Kumar M, Pattnaik BR. Focus on Kir7.1: physiology and channelopathy. Channels. 2015;8:488–495.
  • la Cour M. The retinal pigment epithelium controls the potassium activity in the subretinal space. Acta Ophthalmol Suppl (Oxf.). 1985;173:9–10.
  • Shahi PK, Hermans D, Sinha D, et al., Gene augmentation and readthrough rescue channelopathy in an iPSC-RPE model of congenital blindness. Am J Hum Genet. 2019;104(2): 310–318.
  • Toms M, Bitner-Glindzicz M, Webster A, et al. Usher syndrome: a review of the clinical phenotype, genes and therapeutic strategies. Expert Rev Ophthalmol. 2015;10(3):241–256.
  • Damen GWJA, Beynon AJ, Krabbe PFM, et al. Cochlear implantation and quality of life in postlingually deaf adults: long-term follow-up. Otolaryngol Neck Surg. 2007;136:597–604.
  • Saihan Z, Webster AR, Luxon L, et al. Update on Usher syndrome. Curr Opin Neurol. 2009;22(1):19–27.
  • Nagel-Wolfrum K, Baasov T, Wolfrum U. Therapy Strategies for Usher Syndrome type 1C in the retina. New York, NY: Springer; 2014. p. 741–747.
  • Reiners J, Nagel-Wolfrum K, Jürgens K, et al. Molecular basis of human Usher syndrome: deciphering the meshes of the Usher protein network provides insights into the pathomechanisms of the Usher disease. Exp Eye Res. 2006;83(1):97–119.
  • Neuhaus C, Eisenberger T, Decker C, et al., 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. 2017;5(5): 531–552.
  • Claustres M. Molecular genetic analysis of rare diseases in 2007: selected examples 2007. Research Signpost; 2007.
  • Rebibo-Sabbah A, Nudelman I, Ahmed ZM, et al., In vitro and ex vivo suppression by aminoglycosides of PCDH15 nonsense mutations underlying type 1 Usher syndrome. Hum Genet. 2007;122(3–4): 373–381.
  • Samanta A, Stingl K, Kohl S, et al. Ataluren for the treatment of usher syndrome 2A caused by nonsense mutations. Int J Mol Sci. 2019;20(24).
  • Berlin HS, Ritch R. The treatment of glaucoma secondary aniridia. Mt Sinai J Med. 1981;48(2):111–115.
  • Hingorani M, Williamson KA, Moore AT, et al. Detailed ophthalmologic evaluation of 43 individuals with PAX6 mutations. Investig Ophthalmol Vis Sci. 2009;50(6):2581–2590.
  • Hill RE, Favor J, Hogan BLM, et al. Mouse small eye results from mutations in a paired-like homeobox-containing gene. Nature. 1991;354(6354):522–525.
  • Wang X, Gregory-Evans K, Wasan KM, et al. Efficacy of postnatal in vivo nonsense suppression therapy in a Pax6 mouse model of Aniridia. Mol Ther Nucleic Acids. 2017;7:417–428.
  • Thada V, Miller JN, Kovács AD, et al. Tissue-specific variation in nonsense mutant transcript level and drug-induced read-through efficiency in the Cln1 R151X mouse model of INCL. J Cell Mol Med. 2016;20(2):381–385.
  • Calvo SE, Pagliarini DJ, Mootha VK. Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans. Proc Natl Acad Sci. 2009;106(18):7507–7512.
  • Du M, Liu X, Welch EM, et al. PTC124 is an orally bioavailable compound that promotes suppression of the human CFTR-G542X nonsense allele in a CF mouse model. Proc Natl Acad Sci. 2008;105(6):2064–2069.
  • Schiffelers R. Liposome-encapsulated aminoglycosides in pre-clinical and clinical studies. J Antimicrob Chemother. 2001;48(3):333–344.
  • Barton-Davis ER, Cordier L, Shoturma DI, et al. Aminoglycoside antibiotics restore dystrophin function to skeletal muscles of mdx mice. J Clin Invest. 1999;104(4):375–381.
  • Yukihara M, Ito K, Tanoue O, et al. Effective drug delivery system for duchenne muscular dystrophy using hybrid liposomes including gentamicin along with reduced toxicity. Biol Pharm Bull. 2011;34(5):712–716.
  • Kaji H, Nagai N, Nishizawa M, et al. Drug delivery devices for retinal diseases. Adv Drug Deliv Rev Elsevier B.V. 2018;128:148–157.
  • Cao Y, Samy KE, Bernards DA, et al. Recent advances in intraocular sustained-release drug delivery devices. Drug Discov Today. 2019;24(8):1694–1700.
  • Duong TT, Lim J, Vasireddy V, et al. Comparative AAV-EGFP transgene expression using vector serotypes 1–9, 7M8, and 8b in human pluripotent stem cells, RPEs, and human and rat cortical neurons. Stem Cells Int. 2019;2019.
  • Matsuzono K, Imamura K, Murakami N, et al. Antisense oligonucleotides reduce RNA foci in spinocerebellar Ataxia 36 patient iPSCs. Mol Ther Nucleic Acids. 2017;8:211–219.
  • Zhang Y, Sastre D, Wang F. CRISPR/Cas9 genome editing: a promising tool for therapeutic applications of induced pluripotent stem cells. Curr Stem Cell Res Ther. 2018;13(4):243–251.
  • Wang D, Belakhov V, Kandasamy J, et al. The designer aminoglycoside NB84 significantly reduces glycosaminoglycan accumulation associated with MPS I-H in the Idua-W392X mouse. Mol Genet Metab. 2012;105(1):116–125.
  • Cabrera FJ, Wang DC, Reddy K, et al. Challenges and opportunities for drug delivery to the posterior of the eye. Drug Discov Today. 2019;24(8):1679–1684.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.