Abstract
As our understanding of the genetic basis for inherited retinal disease has expanded, gene therapy has advanced into clinical development. When the gene mutations associated with inherited retinal dystrophies were identified, it became possible to create animal models in which individual gene were altered to match the human mutations. The retina of these animals were then characterized to assess whether the mutated genes produced retinal phenotypes characteristic of disease-affected patients. Following the identification of a subpopulation of patients with the affected gene and the development of techniques for the viral gene transduction of retinal cells, it has become possible to deliver a copy of the normal gene into the retinal sites of the mutated genes. When this was performed in animal models of monogenic diseases, at an early stage of retinal degeneration when the affected cells remained viable, successful gene augmentation corrected the structural and functional lesions characteristic of the specific diseases in the areas of the retina that were successfully transduced. These studies provided the essential proof-of-concept needed to advance monogenic gene therapies into clinic development; these therapies include treatments for: Leber’s congenital amaurosis type 2, caused by mutations to RPE65, retinoid isomerohydrolase; choroideremia, caused by mutations to REP1, Rab escort protein 1; autosomal recessive Stargardt disease, caused by mutations to ABCA4, the photoreceptor-specific ATP-binding transporter; Usher 1B disease caused by mutations to MYO7A, myosin heavy chain 7; X-linked juvenile retinoschisis caused by mutations to RS1, retinoschisin; autosomal recessive retinitis pigmentosa caused by mutations to MERTK, the proto-oncogene tyrosine-protein kinase MER; Leber’s hereditary optic neuropathy caused by mutations to ND4, mitochondrial nicotinamide adenine dinucleotide ubiquinone oxidoreductase (complex I) subunit 4 and achromatopsia, caused by mutations to CNGA3, cyclic nucleotide-gated channel alpha 3 and CNGB3, cyclic nucleotide-gated channel beta 3. This review includes a tabulated summary of treatments for these monogenic retinal dystrophies that have entered into clinical development, as well as a brief summary of the preclinical data that supported their advancement into clinical development.
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Abu-Safieh L, Alrashed M, Anazi S, Alkuraya H, Khan AO, Al-Owain M, Al-Zahrani J, Al-Abdi L, Hashem M, Al-Tarimi S (2013) Autozygome-guided exome sequencing in retinal dystrophy patients reveals pathogenetic mutations and novel candidate disease genes. Genome Res 23:236–247
Acland GM, Aguirre GD, Ray J, Zhang Q, Aleman TS, Cideciyan AV, Pearce-Kelling SE, Anand V, Zeng Y, Maguire AM, Jacobson SG, Hauswirth WW, Bennett J (2001) Gene therapy restores vision in a canine model of childhood blindness. Nat Genet 28(1):92–95
Acland GM, Aguirre GD, Bennett J, Aleman TS, Cideciyan AV, Bennicelli J, Dejneka NS, Pearce-Kelling SE, Maguire AM, Palczewski K, Hauswirth WW, Jacobson SG (2005) 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 12(6):1072–1082
Aguirre GD, Baldwin V, Pearce-Kelling S, Narfstrom K, Ray K, Acland GM (1998) Congenital stationary night blindness in the dog: common mutation in the RPE65 gene indicates founder effect. Mol Vis 4:23–29
Allikmets R, Shroyer NF, Singh N, Seddon JM, Lewis RA, Bernstein PS, Peiffer A, Zabriskie NA, Li Y, Hutchinson A, Dean M, Lupski JR, Leppert M (1997) Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration. Science 277(5333):1805–1807
Allocca M, Doria M, Petrillo M, Colella P, Garcia-Hoyos M, Gibbs D, Kim SR, Maguire A, Rex TS, Di Vicino U, Cutillo L, Sparrow JR, Williams DS, Bennett J, Auricchio A (2008) Serotype-dependent packaging of large genes in adeno-associated viral vectors results in effective gene delivery in mice. J Clin Invest 118(5):1955–1964
Anand V, Barral DC, Zeng Y, Brunsmann F, Maguire AM, Seabra MC, Bennett J (2003) Gene therapy for choroideremia: in vitro rescue mediated by recombinant adenovirus. Vision Res 43:919–926
Bainbridge JW, Mehat MS, Sundaram V, Robbie SJ, Barker SE, Ripamonti C, Georgiadis A, Mowat FM, Beattie SG, Gardner PJ, Feathers KL, Luong VA, Yzer S, Balaggan K, Viswanathan A, de Ravel TJ, Casteels I, Holder GE, Tyler N, Fitzke FW, Weleber RG, Nardini M, Moore AT, Thompson DA, Petersen-Jones SM, Michaelides M, van den Born LI, Stockman A, Smith AJ, Rubin G, Ali RR (2015) Long-term effect of gene therapy on Leber’s congenital amaurosis. N Engl J Med 372:1887–1897
Banin E, Gootwine E, Obolensky A, Ezra-Elia R, Ejzenberg A, Zelinger L, Honig H, Rosov A, Yamin E, Sharon D, Averbukh E, Hauswirth WW, Ofri R (2015) Gene augmentation therapy restores retinal function and visual behavior in a sheep model of CNGA3 achromatopsia. Mol Ther 23(9):1423–1433
Baracca A, Solaini G, Sgarbi G, Lenaz G, Baruzzi A, Schapira AHV, Martinuzzi A, Carelli V (2005) Severe impairment of complex I-driven adenosine triphosphate synthesis in Leber hereditary optic neuropathy cybrids. Arch Neurol 62(5):730–736
Bennett J, Ashtari M, Wellman J, Marshall KA, Cyckowski LL, Chung DC, McCague S, Pierce EA, Chen Y, Bennicelli JL, Zhu X, Ying G-S, Sun J, Wright JF, Auricchio A, Simonelli F, Shindler KS, Mingozzi F, High KA, Maguire AM (2012) AAV2 gene therapy readministration in three adults with congenital blindness. Sci Transl Med 4(120):120ra15
Bennicelli J, Wright JF, Komaromy A, Jacobs JB, Hauck B, Zelenaia O, Mingozzi F, Hui D, Chung D, Rex TS, Wei Z, Qu G, Zhou S, Zeiss C, Arruda VR, Acland GM, Dell’Osso LF, High KA, Maguire AM, Bennett J (2008) Reversal of blindness in animal models of Leber congenital amaurosis using optimized AAV2-mediated gene transfer. Mol Ther 16(3):458–465
Berson EL (2007) Long-term visual prognoses in patients with retinitis pigmentosa: the Ludwig von Sallmann lecture. Exp Eye Res 85(1):7–14
Binley K, Widdowson P, Loader J, Kelleher M, Iqball S, Ferrige G, de Belin J, Carlucci M, Angell-Manning D, Hurst F, Ellis S, Miskin J, Fernandes A, Wong P, Allikmets R, Bergstrom C, Aaberg T, Yan J, Kong J, Gouras P, Prefontaine A, Vezina M, Bussieres M, Naylor S, Mitrophanous KA (2013) Transduction of photoreceptors with EIAV lentiviral vectors; safety and biodistribution of StarGen for Stargardt disease. Invest Ophthalmol Vis Sci 54(6):4061–4071
Black A, Vasireddy V, Chung DC, Maguire AM, Gaddameedi R, Tolmachova T, Seabra M, Bennett J (2014) Adeno-associated virus 8-mediated gene therapy for choroideremia: preclinical studies in in vitro and in vivo models. J Gene Med 16:122–130
Bourne MC, Campbell DA, Tansley K (1938) Hereditary degeneration of the rat retina. Br J Ophthalmol 22(10):613–623
Braun TA, Mullins RF, Wagner AH, Andorf JL, Johnston RM, Bakall BB, Deluca AP, Fishman GA, Lam BL, Weleber RG, Cideciyan AV, Jacobson SG, Sheffield VC, Tucker BA, Stone EM (2013) Non-exomic and synonymous variants in ABCA4 are an important cause of Stargardt disease. Hum Mol Genet 22(25):5136–5145
Brown MD, Trounce IA, Jun AS, Allen JC, Wallace DC (2000) Functional analysis of lymphoblast and cybrid mitochondria containing the 3460, 11778, or 14484 Leber’s hereditary optic neuropathy mitochondrial DNA mutation. J Biol Chem 275(51):39831–39836
Cai X, Conley SM, Naash MI (2009) RPE65: role in the visual cycle, human retinal disease, and gene therapy. Ophthalmic Genet 30(2):57–62
Carelli V, La Morgia C, Valentino ML, Barboni P, Ross-Cisneros FN, Sadun AA (2009) Retinal ganglion cell neurodegeneration in mitochondrial inherited disorders. Biochim Biophys Acta 1787(5):518–528
Carvalho LS, Xu J, Pearson RA, Smith AJ, Bainbridge JW, Morris LM, Fliesler SJ, Ding X-Q, Ali RR (2011) Long-term and age-dependent restoration of visual function in a mouse model of CNGB3-associated achromatopsia following gene therapy. Hum Mol Genet 20(16):3161–3175
Chacon-Camacho OF, Zenteno JC (2015) Review and update on the molecular basis of Leber congenital amaurosis. World J Clin Cases 3(2):112–124
Chang B, Hawes NL, Hurd RE, Davisson MT, Nusinowitz S, Heckenlively JR (2002) Retinal degeneration mutants in the mouse. Vision Res 42(4):517–525
Charbel P, Bolz HJ, Ebermann I, Domeier E, Holz FG, Scholl HP (2009) Characterization of severe rod-cone dystrophy in a consanguineous family with a splice site mutation in the MERTK gene. Br J Ophthalmol 93:920–925
Chinnery PF, Andrews RM, Turnbull DM, Howell NN (2001) Leber hereditary optic neuropathy: does heteroplasmy influence the inheritance and expression of the G11778A mitochondrial DNA mutation? Am J Med Genet 98:235–243
Cideciyan AV, Jacobson SG, Beltran WA, Sumaroka A, Swider AM, Iwabe S, Roman AJ, Olivares MB, Schwartz SB, Komaromy AM, Hauswirth WW, Aguirre GD (2013) Human retinal gene therapy for Leber congenital amaurosis shows advancing retinal degeneration despite enduring visual improvement. Proc Natl Acad Sci U S A 110(6):E517–E525
Conlon TJ, Deng WT, Erger K, Cossette T, Pang J, Ryals R, Clement N, Cleaver B, McDoom I, Boye SE, Peden MC, Sherwood MB, Abernathy CR, Alkuraya FS, Boye SL, Hauswirth WW (2013) 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 24(1):23–28
Cwerman-Thibault H, Augustin S, Lechauve C, Ayache J, Ellouze S, Sahel JA, Corral-Debrinski M (2015) Nuclear expression of mitochondrial ND4 leads to the protein assembling in complex I and prevents optic atrophy and visual loss. Mol Ther Methods Clin Dev 2:15003. doi:10.1038/mtm.2015.3
D’Cruz PM, Yasumura D, Weir J, Matthes MT, Abderrahim H, LaVail MM, Vollrath D (2000) Mutation of the receptor tyrosine kinase gene Mertk in the retinal dystrophic RCS rat. Hum Mol Genet 9(4):645–651
Dong B, Nakai H, Xiao W (2010) Characterization of genome integrity for oversized recombinant AAV vector. Mol Ther 18(1):87–92
Dryja TP, McGee TL, Reichel E, Hahn LB, Cowley GS, Yandell DW, Sandberg MA, Berson EL (1990) A point mutation of the rhodopsin gene in one form of retinitis pigmentosa. Nature 343(6256):364–366
Duan D, Yue Y, Engelhardt JF (2001) Expanding AAV packaging capacity with trans-splicing or overlapping vectors: a quantitative comparison. Mol Ther 4(4):383–391
Duncan JL, LaVail MM, Yasumura D, Matthes MT, Yang H, Trautmann N, Chappelow AV, Feng W, Earp WS, Matsushima GK, Vollrath D (2003) An RCS-like retinal dystrophy phenotype in mer knockout mice. Invest Ophthalmol Vis Sci 44:826–838
Dyka FM, Boye SL, Chiodo VA, Hauswirth WW, Boye SE (2014) Dual adeno-associated virus vectors result in efficient in vitro and in vivo expression of an oversized gene, MYO7A. Hum Gene Ther Methods 25(2):166–177
Edwards TL, Jolly JK, Groppe M, Barnard AR, Cottriall CL, Tolmachova T, Black GC, Webster AR, Lotery AJ, Holder GE, Xue K, Downe SM, Simunovic MP, Seabra MC, MacLaren RE (2016) Visual acuity after retinal gene therapy for choroideremia. N Engl J Med 374(20):1996–1998
Ellouze S, Augustin S, Bouaita A, Bonnet C, Simonutti M, Forster V, Picaud S, Sahel JA, Corral-Debrinski M (2008) Optimized allotopic expression of the human mitochondrial ND4 prevents blindness in a rat model of mitochondrial dysfunction. Am J Hum Genet 83(3):373–387
Farber DB, Lolley RN (1976) Enzymic basis for cyclic GMP accumulation in degenerative photoreceptor cells of mouse retina. J Cyclic Nucleotide Res 2(3):139–148
Feathers KL, Lyubarsky AL, Khan NW, Teofilo K, Swaroop A, Williams DS, Pugh EN Jr, Thompson DA (2008) Nrl-knockout mice deficient in Rpe65 fail to synthesize 11-cis retinal and cone outer segments. Invest Ophthalmol Vis Sci 49(3):1126–1135
Feuer WJ, Schiffman JC, Davis JL, Porciatti V, Gonzalez P, Koilkonda RD, Yuan H, Lalwani A, Lam BL, Guy J (2016) Gene therapy for Leber hereditary optic neuropathy: initial results. Ophthalmology 123(3):558–570
Freund PR, Sergeev YV, MacDonald IM (2016) 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 4(3):344–358
Gal A, Li Y, Thompson DA, Weir J, Orth U, Jacobson SG, Apfelstedt-Sylla E, Vollrath D (2000) Mutations in MERTK, the human orthologue of the RCS rat retinal dystrophy gene, cause retinitis pigmentosa. Nat Genet 26:270–271
Ghazi NG, Abboud EB, Nowilaty SR, Alkuraya H, Alhommadi A, Cai H, Hou R, Deng W-T, Boye SL, Almaghamsi A, Saikhan FA, Al-Dhibi H, Birch D, Chung C, Colak D, LaVail MM, Vollrath D, Erger K, Wang W, Conlon T, Zhang K, Hauswirth W, Alkuraya FS (2016) 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 135(3):327–343
Ghosh A, Yue Y, Lai Y, Duan D (2008) A hybrid vector system expands adeno-associated viral vector packaging capacity in a transgene-independent manner. Mol Ther 16(1):124–130
Gibbs D, Kitamoto J, Williams DS (2003) Abnormal phagocytosis by retinal pigmented epithelium that lacks myosin VIIa, the Usher syndrome 1B protein. Proc Natl Acad Sci U S A 100(11):6481–6486
Gibson F, Walsh J, Mburu P, Varela A, Brown KA, Antonio M, Beisel KW, Steel KP, Brown SD (1995) A type VII myosin encoded by the mouse deafness gene shaker-1. Nature 374(6517):62–64
Graham DK, Dawson TL, Mullaney DL, Snodgrass HR, Earp HS (1994) Cloning and mRNA expression analysis of a novel human protooncogene, c-mer. Cell Growth Differ 5(6):647–657
Haer-Wigman L, Newman H, Leibu R, Bax NM, Baris HN, Rizel L, Banin E, Massarweh A, Roosing S, Lefeber DJ, Zonneveld-Vrieling MN, Isakov O, Shomron N, Sharon D, Den Hollander AI, Hoyng CB, Cremers FPM, Ben-Yosef T (2015) Non-syndromic retinitis pigmentosa due to mutations in the mucopolysaccharidosis type IIIC gene, heparan-alpha-glucosaminide N-acetyltransferase (HGSNAT). Hum Mol Genet 24(13):3742–3751
Hafezi F, Grimm C, Simmen B, Wenzel A, Reme C (2000) Molecular ophthalmology: an update on animal models for retinal degenerations and dystrophies. Br J Ophthalmol 84(8):922–927
Hashimoto T, Gibbs D, Lillo C, Azarian SM, Legacki E, Zhang XM, Yang XJ, Williams DS (2007) Lentiviral gene replacement therapy of retinas in a mouse model for Usher syndrome type 1B. Gene Ther 14(7):584–594
Jacobson SG, Boye SL, Aleman TS, Conlon TJ, Zeiss CJ, Roman AJ, Cideciyan AV, Schwartz SB, Komaromy AM, Doobrajh M, Cheung AY, Sumaroka A, Pearce-Kelling SE, Aguirre GD, Kaushal S, Maguire AM, Flotte TR, Hauswirth WW (2006) Safety in nonhuman primates of ocular AAV2-RPE65, a candidate treatment for blindness in Leber congenital amaurosis. Hum Gene Ther 17(8):845–858
Jacobson SG, Cideciyan AV, Ratnakaram R, Heon E, Schwartz SB, Roman AJ, Peden MC, Aleman TS, Boye SL, Sumaroka A, Conlon TJ, Calcedo R, Pang JJ, Erger KE, Olivares MB, Mullins CL, Swider M, Kaushal S, Feuer WJ, Iannaccone A, Fishman GA, Stone EM, Byrne BJ, Hauswirth WW (2012) Gene therapy for Leber congenital amaurosis caused by RPE65 mutations: safety and efficacy in 15 children and adults followed up to 3 years. Arch Ophthalmol 130(1):9–24
Jacobson SG, Cideciyan AV, Roman AJ, Sumaroka A, Schwartz SB, Heon E, Hauswirth WW (2015) Improvement and decline in vision with gene therapy in childhood blindness. N Engl J Med 372:1920–1926
Janssen A, Min SH, Molday LL, Tanimoto N, Seeliger MW, Hauswirth WW, Molday RS, Weber BH (2008) Effect of late-stage therapy on disease progression in AAV-mediated rescue of photoreceptor cells in the retinoschisin-deficient mouse. Mol Ther 16(6):1010–1017
Kaminski WE, Piehler A, Wenzel JJ (2006) ABC A-subfamily transporters: structure, function and disease. Biochim Biophys Acta 1762(5):510–524
Khan NW, Wissinger B, Kohl S, Sieving PA (2007) CNGB3 achromatopsia with progressive loss of residual cone function and impaired rod-mediated function. Invest Ophthalmol Vis Sci 48:3864–3871
Kimberling WJ, Hildebrand MS, Shearer AE, Jensen ML, Halder JA, Trzupek K, Cohn ES, Weleber RG, Stone EM, Smith RJ (2010) Frequency of Usher syndrome in two pediatric populations: implications for genetic screening of deaf and hard of hearing children. Genet Med 12:512–516
Kirches E (2011) LHON: mitochondrial mutations and more. Curr Genomics 12:44–54
Kjellstrom S, Bush RA, Zeng Y, Takada Y, Sieving PA (2007) Retinoschisin gene therapy and natural history in the Rs1h-KO mouse: long-term rescue from retinal degeneration. Invest Ophthalmol Vis Sci 48:3837–3845
Kohl S, Baumann B, Broghammer M, Jagle H, Sieving P, Kellner U, Spegal R, Anastasi M, Zrenner E, Sharpe LT, Wissinger B (2000) Mutations in the CNGB3 gene encoding the beta-subunit of the cone photoreceptor cGMP-gated channel are responsible for achromatopsia (ACHM3) linked to chromosome 8q21. Hum Mol Genet 9:2107–2116
Kohl S, Varsanyi B, Antunes GA, Baumann B, Hoyng CB, Jägle H, Rosenberg T, Kellner U, Lorenz B, Salati R, Jurklies B, Farkas A, Andreasson S, Weleber RG, Jacobson SG, Rudolph G, Castellan C, Dollfus H, Legius E, Anastasi M, Bitoun P, Lev D, Sieving PA, Munier FL, Zrenner E, Sharpe LT, Cremers FP, Wissinger B (2005) CNGB3 mutations account for 50% of all cases with autosomal recessive achromatopsia. Eur J Hum Genet 13(3):302–308
Koilkonda R, Yu H, Talla V, Porciatti V, Feuer WJ, Hauswirth WW, Chiodo V, Erger KE, Boye SL, Lewin AS, Conlon TJ, Renner L, Neuringer M, Detrisac C, Guy J (2014) LHON gene therapy vector prevents visual loss and optic neuropathy induced by G11778A mutant mitochondrial DNA: biodistribution and toxicology profile. Invest Ophthalmol Vis Sci 55(12):7739–7753
Komaromy AM, Alexander JJ, Rowlan JS, Garcia MM, Chiodo VA, Kaya A, Tanaka JC, Acland GM, Hauswirth WW, Aguirre GD (2010) Gene therapy rescues cone function in congenital achromatopsia. Hum Mol Genet 19:2581–2593
Kong J, Kim SR, Binley K, Pata I, Doi K, Mannik J, Zernant-Rajang J, Kan O, Iqball S, Naylor S, Sparrow JR, Gouras P, Allikmets R (2008) Correction of the disease phenotype in the mouse model of Stargardt disease by lentiviral gene therapy. Gene Ther 15(19):1311–1320
Lai Y, Yue Y, Duan D (2010) Evidence for the failure of adeno-associated virus serotype 5 to package a viral genome > or = 8.2 kb. Mol Ther 18(1):75–79
LaVail MM, Yasumura D, Matthes MT, Yang H, Hauswirth WW, Deng WT, Vollrath D (2016) Gene therapy for MERTK-associated retinal degenerations. Adv Exp Med Biol 854:487–493
Le Meur G, Stieger K, Smith AJ, Weber M, Deschamps JY, Nivard D, Mendes-Madeira A, Provost N, Péréon Y, Cherel Y, Ali RR, Hamel C, Moullier P, Rolling F (2007) Restoration of vision in RPE65-deficient Briard dogs using an AAV serotype 4 vector that specifically targets the retinal pigmented epithelium. Gene Ther 14:292–303
Lentz J, Keats BJB (2016) Usher syndrome type I. In: Pagon RA, Adam MP, Ardinger HH et al (eds) GeneReviews® [Internet]. University of Washington, Seattle, pp 1993–2016 10 Dec 1999 [Updated 19 May 2016]
Li J, Sun W, Wang B, Xiao X, Liu XQ (2008) Protein trans-splicing as a means for viral vector-mediated in vivo gene therapy. Hum Gene Ther 19(9):958–964
Li Q, Miller R, Han PY, Pang J, Dinculescu A, Chiodo V, Hauswirth WW (2008) Intraocular route of AAV2 vector administration defines humoral immune response and therapeutic potential. Mol Vis 14:1760–1769
Li W, Kong F, Li X, Dai X, Liu X, Zheng Q, Wu R, Zhou X, Lü F, Chang B, Li Q, Hauswirth WW, Qu J, Pang JJ (2009) Gene therapy following subretinal AAV5 vector delivery is not affected by a previous intravitreal AAV5 vector administration in the partner eye. Mol Vis 15:267–275
Libby RT, Steel KP (2001) Electroretinographic anomalies in mice with mutations in Myo7a, the gene involved in human Usher syndrome type 1B. Invest Ophthalmol Vis Sci 42(3):770–778
Lin CS, Sharpley MS, Fan W, Waymire KG, Sadun AA, Carelli V, Ross-Cisneros FN, Baciu P, Sung E, McManus MJ, Pan BX, Gil DW, Macgregor GR, Wallace DC (2012) Mouse mtDNA mutant model of Leber hereditary optic neuropathy. Proc Natl Acad Sci U S A 109(49):20065–20070
Lin H-Z, Pang C-Y, Chen S-P, Tsai R-K (2012) Vision improvement in a Taiwanese (Han Chinese) family with Leber’s hereditary optic neuropathy. Kaohsiung J Med Sci 28:679–682
Liu X, Ondek B, Williams DS (1998) Mutant myosin VIIa causes defective melanosome distribution in the RPE of shaker-1 mice. Nat Genet 19(2):117–118
Liu X, Udovichenko IP, Brown SD, Steel KP, Williams DS (1999) Myosin VIIa participates in opsin transport through the photoreceptor cilium. J Neurosci 19(15):6267–6274
MacDonald IM, Mah DY, Ho YK, Lewis RA, Seabra MC (1998) A practical diagnostic test for choroideremia. Ophthalmology 105(9):1637–1640
MacDonald IM, Hume S, Chan S, Sebra MC (2003) Choroideremia. In: Pagon RA, Adam MP, Ardinger HH et al (eds) GeneReviews® [Internet]. University of Washington, Seattle, pp 1993–2016
Mackay DS, Henderson RH, Sergouniotis PI, Li Z, Moradi P, Holder GE, Waseem N, Bhattacharya SS, Aldahmesh MA, Alkuraya FS, Meyer B, Webster AR, Moore AT (2010) Novel mutations in MERTK associated with childhood onset rod- cone dystrophy. Mol Vis 16:369–377
MacLaren RE, Groppe M, Barnard AR, Cottriall CL, Tolmachova T, Seymour L, Clark KR, During MJ, Cremers FPM, Black GCM, Lotery AJ, Downes SM, Webster AR, Seabra MC (2014) Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial. Lancet 383(9923):1129–1137
Maeda A, Maeda T, Golczak M, Palczewski K (2008) Retinopathy in mice induced by disrupted all-trans-retinal clearance. J Biol Chem 283(39):26684–26693
MaGuire W (2005) Human gene transfer protocol #740 – a Phase I safety study in subjects with Leber Congenital Amaurosis (LCA) using adeno-associated viral vector to deliver the gene for human RPE65 into the Retinal Pigment Epithelium (RPE). FDA OBA Presentation
Man PY, Griffiths PG, Brown DT, Howell N, Turnbull DM, Chinnery PF (2003) The epidemiology of Leber hereditary optic neuropathy in the North East of England. Am J Hum Genet 72(2):333–339
Man PYW, Turnbull DM, Chinnery PF (2002) Leber hereditary optic neuropathy. J Med Genet 39:162–169
Michalakis S, Mühlfriedel R, Tanimoto N, Krishnamoorthy V, Koch S, Fischer MD, Becirovic E, Bai L, Huber G, Beck SC, Fahl E, Buning H, Paquet-Durand F, Zong X, Gollisch T, Biel M, Seeliger MW (2010) Restoration of cone vision in the CNGA3−/− mouse model of congenital complete lack of cone photoreceptor function. Mol Ther 18(12):2057–2063
Molday LL, Hicks D, Sauer CG, Weber BH, Molday RS (2001) Expression of X-linked retinoschisis protein RS1 in photoreceptor and bipolar cells. Invest Ophthalmol Vis Sci 42:816–825
Molday RS, Kellner U, Weber BHF (2012) X-linked juvenile retinoschisis: Clinical diagnosis, genetic analysis, and molecular mechanisms. Prog Retin Eye Res 3:195–212 195e212
Narfstrom K, Vaegan, Katz M, Bragadottir R, Rakoczy EP, Seeliger M (2005) Assessment of structure and function over a 3-year period after gene transfer in RPE65-/- dogs. Doc Ophthalmol 111:39–48
Orhan E, Dalkara D, Neuillé M, Lechauve C, Michiels C, Picaud S, Léveillard T, Sahel JA, Naash MI, Lavail MM, Zeitz C, Audo I (2015) Genotypic and phenotypic characterization of P23H line 1 rat model. PLoS One 10(5):e0127319
Pang JJ, Chang B, Hawes NL, Hurd RE, Davisson MT, Li J, Noorwez SM, Malhotra R, McDowell JH, Kaushal S, Hauswirth WW, Nusinowitz S, Thompson DA, Heckenlively JR (2005) Retinal degeneration 12 (rd12): a new, spontaneously arising mouse model for human Leber congenital amaurosis (LCA). Mol Vis 11:152–162
Park TK, Wu Z, Kjellstrom S, Zeng Y, Bush RA, Sieving PA, Colosi P (2009) Intravitreal delivery of AAV8 retinoschisin results in cell type-specific gene expression and retinal rescue in the Rs1-KO mouse. Gene Ther 16(7):916–926
Patel N, Aldahmesh MA, Alkuraya H, Anazi S, Alsharif H, Khan AO, Sunker A, Al-Mohsen S, Abboud EB, Nowilaty SR, Alowain M, Al-Zaidan H, Al-Saud B, Alasmari A, Abdel-Salam GM, Abouelhoda M, Abdulwahab FM, Ibrahim N, Naim E, Al-Younes B, E AlMostafa A, AlIssa A, Hashem M, Buzovetsky O, Xiong Y, Monies D, Altassan N, Shaheen R, Al-Hazzaa SA, Alkuraya FS (2015) Expanding the clinical, allelic, and locus heterogeneity of retinal dystrophies. Genet Med 18(6):554–562
Pearson RA, Hippert C, Graca AB, Barber AC (2014) Photoreceptor replacement therapy: challenges presented by the diseased recipient retinal environment. Vis Neurosci 31(4–5):333–344
Peng C, Rich ED, Varnum MD (2004) Subunit configuration of heteromeric cone cyclic nucleotide-gated channels. Neuron 42:401–410
Peng YW, Zallocchi M, Wang WM, Delimont D, Cosgrove D (2011) Moderate light-induced degeneration of rod photoreceptors with delayed transducin translocation in shaker1 mice. Invest Ophthalmol Vis Sci 52(9):6421–6427
Petrs-Silva H, Linden R (2014) Advances in gene therapy technologies to treat retinitis pigmentosa. Clin Ophthalmol 8:127–136
Puomila A, Hämäläinen P, Kivioja S, Savontaus ML, Koivumäki S, Huoponen K, Nikoskelainen E (2007) Epidemiology and penetrance of Leber hereditary optic neuropathy in Finland. Eur J Hum Genet 15(10):1079–1089
Qi X, Sun L, Lewin AS, Hauswirth WW, Guy J (2007) The mutant human ND4 subunit of complex I induces optic neuropathy in the mouse. Invest Ophthalmol Vis Sci 48:1–10
Redmond TM, Yu S, Lee E, Bok D, Hamasaki D, Chen N, Goletz P, Ma JX, Crouch RK, Pfeifer K (1998) Rpe65 is necessary for production of 11-cis-vitamin A in the retinal visual cycle. Nat Genet 20(4):344–351
Reich SJ, Auricchio A, Hildinger M, Glover E, Maguire AM, Wilson JM, Bennett J (2003) Efficient trans-splicing in the retina expands the utility of adeno-associated virus as a vector for gene. Hum Gene Ther 14(1):37–44
Rohrer B, Goletz P, Znoiko S, Ablonczy Z, Ma J-X, Redmond TM, Crouch RK (2003) Correlation of regenerable opsin with rod ERG signal Rpe65-/- mice during development and aging. Invest Ophthalmol Vis Sci 44:310–315
Ross JW, Fernandez de Castro JP, Zhao J, Samuel M, Walters E, Rios C, Bray-Ward P, Jones BW, Marc RE, Wang W, Zhou L, Noel JM, McCall MA, DeMarco PJ, Prather RS, Kaplan HJ (2012) Generation of an inbred miniature pig model of retinitis pigmentosa. Invest Ophthalmol Vis Sci 53(1):501–507
Sahel J-A, Marazova K, Audo I (2015) Clinical characteristics and current therapies for inherited retinal degenerations. Cold Spring Harb Perspect Med. doi:10.1101/cshperspect.a017111
Sala G, Trombin F, Beretta S, Tremolizzo L, Presutto P, Montopoli M, Fantin M, Martinuzzi A, Carelli V, Ferrarese C (2008) Antioxidants partially restore glutamate transport defect in Leber hereditary optic neuropathy cybrids. J Neurosci Res 86(15):3331–3337
Sauer CG, Gehrig A, Warneke-Wittstock R, Marquardt A, Ewing CC, Gibson A, Lorenz B, Jurklies B, Weber BH (1997) Positional cloning of the gene associated with X-linked juvenile retinoschisis. Nat Genet 17:164–170
Schindler EI, Nylen EL, Ko AC, Affatigato LM, Heggen AC, Wang K, Sheffield VC, Stone EM (2010) Deducing the pathogenic contribution of recessive ABCA4 alleles in an outbred population. Hum Mol Genet 19(19):3693–3701
Smith KH, Johns DR, Heher KL, Miller NR (1993) Heteroplasmy in Leber’s hereditary optic neuropathy. Arch Ophthalmol 111(11):1486–1490
Song D, Grieco S, Li Y, Hunter Chu AS, Zhao L, Song Y, DeAngelis RA, Shi LY, Liu Q, Pierce EA, Nishina PM, Lambris JD, Dunaief JL (2014) A murine rp1 missense mutation causes protein mislocalization and slowly progressive photoreceptor degeneration. Am J Pathol 184(10):2721–2729
Sowden JC (2015) Developing stem cell therapy for retinal dystrophies. Cilia 4(Suppl 1):O19
Sun H, Nathans J (2000) ABCR: rod photoreceptor-specific ABC transporter responsible for Stargardt disease. Methods Enzymol 315:879–897
Tada A, Wada Y, Sato H, Itabashi T, Kawamura M, Tamai M, Nishida K (2006) Screening of the MERTK gene for mutations in Japanese patients with autosomal recessive retinitis pigmentosa. Mol Vis 12:441–444
Takada Y, Vijayasarathy C, Zeng Y, Kjellstrom S, Bush RA, Sieving PA (2008) Synaptic pathology in retinoschisis knockout (Rs1-/y) mouse retina and modification by rAAV-Rs1 gene delivery. Invest Ophthalmol Vis Sci 49:3677–3686
Tamayo ML, Bernal JE, Tamayo GE, Frias JL, Alvira G, Vergara O, Rodriguez V, Uribe JI, Silva JC (1991) Usher syndrome: results of a screening program in Colombia. Clin Genet 40:304–311
Tang Y, Wu S, Liu Q, Xie J, Zhang J, Han D, Lu Q, Lu Q (2015) Mertk deficiency affects macrophage directional migration via disruption of cytoskeletal organization. PLoS One 10(1):e0117787
Tantri A, Vrabec TR, Cu-Unjieng A, Frost A, Annesley WH Jr, Donoso LA (2004) X-linked retinoschisis: a clinical and molecular genetic review. Surv Ophthalmol 49:214–230
Thompson DA, Gyürüs P, Fleischer LL, Bingham EL, McHenry CL, Apfelstedt-Sylla E, Zrenner E, Lorenz B, Richards JE, Jacobson SG, Sieving PA, Gal A (2000) Genetics and phenotypes of RPE65 mutations in inherited retinal degeneration. Invest Ophthalmol Vis Sci 41(13):4293–4299
Thompson DA, Ali RR, Banin E, Branham KE, Flannery JG, Gamm DM, Hauswirth WW, Heckenlively JR, Iannaccone A, Jayasundera KT, Khan NW, Molday RS, Pennesi ME, Reh TA, Weleber RG, Zacks DN, Monaciano Consortium (2015) Advancing therapeutic strategies for inherited retinal degeneration: recommendations from the Monaciano Symposium. Invest Ophthalmol Vis Sci 56(2):918–931
Tolmachova T, Anders R, Abrink M, Bugeon L, Dallman MJ, Futter CE, Ramalho JS, Tonagel F, Tanimoto N, Seeliger MW, Huxley C, Seabra MC (2006) Independent degeneration of photoreceptors and retinal pigment epithelium in conditional knockout mouse models of choroideremia. J Clin Invest 116(2):386–394
Travis GH, Golczak M, Moise AR, Palczewski K (2007) Diseases caused by defects in the visual cycle: retinoids as potential therapeutic agents. Annu Rev Pharmacol Toxicol 47:469–512
Tucker BA, Mullins RF, Stone EM (2014) Stem cells for investigation and treatment of inherited retinal disease. Hum Mol Genet 23(R1):R9–R16
van den Hurk JA, Hendriks W, van de Pol DJ, Oerlemans F, Jaissle G, Rüther K, Kohler K, Hartmann J, Zrenner E, van Bokhoven H, Wieringa B, Ropers HH, Cremers FP (1997) Mouse choroideremia gene mutation causes photoreceptor cell degeneration and is not transmitted through the female germline. Hum Mol Genet 6:851–858
Vasireddy V, Mills JA, Gaddameedi R, Basner-Tschakarjan E, Kohnke M, Black AD, Alexandrov K, Zhou S, Maguire AM, Chung DC, Mac H, Sullivan L, Gadue P, Bennicelli JL, French DL, Bennett J (2013) AAV-mediated gene therapy for choroideremia: preclinical studies in personalized models. PLoS One 8(5):e61396
Veleri S, Lazar CH, Chang B, Sieving PA, Banin E, Swaroop A (2015) Biology and therapy of inherited retinal degenerative disease: insights from mouse models. Dis Model Mech 8(2):109–129
Vesk A, Nilsson SEG, Narfstrom K, Gal A (1999) Retinal dystrophy of Swedish briard/briard-beagle dogs is due to a 4-bp deletion in RPE65. Genomics 57:57–61
Vollrath D, Feng W, Duncan JL, Yasumura D, D’Cruz PM, Chappelow A, Matthes MT, Kay MA, LaVail MM (2001) Correction of the retinal dystrophy phenotype of the RCS rat by viral gene transfer of Mertk. Proc Natl Acad Sci U S A 98(22):12584–12589
Weleber RG, Francis PJ, Trzupek KM et al (2013) Leber congenital amaurosis. In: Pagon RA, Adam MP, Ardinger HH et al (eds) GeneReviews® [Internet]. University of Washington, Seattle, pp 1993–2016
Weng J, Mata NL, Azarian SM, Tzekov RT, Birch DG, Travis GH (1999) Insights into the function of Rim protein in photoreceptors and etiology of Stargardt’s disease from the phenotype in abcr knockout mice. Cell 98(1):13–23
Wissinger B, Gamer D, Jägle H, Giorda R, Marx T, Mayer S, Tippmann S, Broghammer M, Jurklies B, Rosenberg T, Jacobson SG, Sener EC, Tatlipinar S, Hoyng CB, Castellan C, Bitoun P, Andreasson S, Rudolph G, Kellner U, Lorenz B, Wolff G, Verellen-Dumoulin C, Schwartz M, Cremers FP, Apfelstedt-Sylla E, Zrenner E, Salati R, Sharpe LT, Kohl S (2001) CNGA3 mutations in hereditary cone photoreceptor disorders. Am J Hum Genet 69(4):722–737
Wu Z, Yang H, Colosi P (2010) Effect of genome size on AAV vector packaging. Mol Ther 18(1):80–86
Yanoff M, Duker JS (2008) Ophthalmology, 3rd edn. Mosby, Edinburgh, pp 560–562
Zallocchi M, Binley K, Lad Y, Ellis S, Widdowson P, Iqball S, Scripps V, Kelleher M, Loader J, Miskin J, Peng Y-W, Wang W-M, Cheung L, Delimont D, Mitrophanous KA, Cosgrove D (2014) EIAV-based retinal gene therapy in the mouse model for Usher syndrome type 1B: development of UshStat. PLoS One 9(4):e94272
Zeng Y, Takada Y, Kjellstrom S, Hiriyanna K, Tanikawa A, Wawrousek E, Smaoui N, Caruso R, Bush RA, Sieving PA (2004) RS-1 gene delivery to an adult Rs1h knockout mouse model restores ERG b-wave with reversal of the electronegative waveform of X-linked retinoschisis. Invest Ophthalmol Vis Sci 45:3279–3285
Acknowledgments
The Foundation Fighting Blindness, Columbia, Maryland, was extremely helpful during the writing of this review. Brian Mansfield, PhD and Stephen Rose, PhD generously shared their extensive knowledge of inherited retinal dystrophies and Brian Mansfield, PhD critically reviewed the manuscript.
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Hohman, T.C. (2016). Hereditary Retinal Dystrophy. In: Whitcup, S., Azar, D. (eds) Pharmacologic Therapy of Ocular Disease. Handbook of Experimental Pharmacology, vol 242. Springer, Cham. https://doi.org/10.1007/164_2016_91
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