Hostname: page-component-5db58dd55d-htx7c Total loading time: 0 Render date: 2026-05-26T14:24:17.609Z Has data issue: false hasContentIssue false
  • English
  • Français

Gene therapies for inherited retinal disorders

Published online by Cambridge University Press:  20 June 2014

G. JANE FARRAR ,
SOPHIA MILLINGTON-WARD ,
NAOMI CHADDERTON ,
FIONA C. MANSERGH  and
ARPAD PALFI
G. JANE FARRAR*
Affiliation:
Smurfit Institute of Genetics, School of Genetics and Microbiology, Trinity College Dublin, Dublin 2, Ireland
SOPHIA MILLINGTON-WARD
Affiliation:
Smurfit Institute of Genetics, School of Genetics and Microbiology, Trinity College Dublin, Dublin 2, Ireland
NAOMI CHADDERTON
Affiliation:
Smurfit Institute of Genetics, School of Genetics and Microbiology, Trinity College Dublin, Dublin 2, Ireland
FIONA C. MANSERGH
Affiliation:
Smurfit Institute of Genetics, School of Genetics and Microbiology, Trinity College Dublin, Dublin 2, Ireland
ARPAD PALFI
Affiliation:
Smurfit Institute of Genetics, School of Genetics and Microbiology, Trinity College Dublin, Dublin 2, Ireland
Get access Rights & Permissions [Opens in a new window]

Abstract

Significant advances have been made over the last decade or two in the elucidation of the molecular pathogenesis of inherited ocular disorders. In particular, remarkable successes have been achieved in exploration of gene-based medicines for these conditions, both in preclinical and in clinical studies. Progress in the development of gene therapies targeted toward correcting the primary genetic defect or focused on modulating secondary effects associated with retinal pathologies are discussed in the review. Likewise, the recent utilization of genes encoding light-sensing molecules to provide new functions to residual retinal cells in the degenerating retina is discussed. While a great deal has been learned over the last two decades, the next decade should result in an increasing number of preclinical studies progressing to human clinical trial, an exciting prospect for patients, those active in research and development and bystanders alike.

Keywords

Gene therapyRetinal degenerationsAdeno-associated virusRNA interferenceOptogenetics

Information

Type
Review Articles
Information
Visual Neuroscience , Volume 31 , Issue 4-5: Strategies for Restoring Sight in Retinal Dystrophies , September 2014 , pp. 289 - 307
Copyright
Copyright © Cambridge University Press 2014 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Article purchase

Temporarily unavailable

References

Acland, G.M., Aguirre, G.D., Bennett, J., Aleman, T.S., Cideciyan, A.V., Bennicelli, J., Dejneka, N.S., Pearce-Kelling, S.E., Maguire, A.M., Palczewski, K., Hauswirth, W.W. & Jacobson, S.G. (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. Molecular Therapy 12, 1072–1082.Google Scholar
Acland, G.M., Aguirre, G.D., Ray, J., Zhang, Q., Aleman, T.S., Cideciyan, A.V., Pearce-Kelling, S.E., Anand, V., Zeng, Y., Maguire, A.M., Jacobson, S.G., Hauswirth, W.W. & Bennett, J. (2001). Gene therapy restores vision in a canine model of childhood blindness. Nature Genetics 28, 92–95.Google Scholar
Aguilà, M., Bevilacqua, D., McCulley, C., Schwarz, N., Athanasiou, D., Kanuga, N., Novoselov, S.S., Lange, C.A., Ali, R.R., Bainbridge, J.W., Gias, C., Coffey, P.J., Garriga, P. & Cheetham, M.E. (2014). Hsp90 inhibition protects against inherited retinal degeneration. Human Molecular Genetics 23, 2164–2175.Google Scholar
Alexander, J.J., Umino, Y., Everhart, D., Chang, B., Min, S.H., Li, Q., Timmers, A.M., Hawes, N.L., Pang, J.J., Barlow, R.B. & Hauswirth, W.W. (2007). Restoration of cone vision in a mouse model of achromatopsia. Nature Medicine 13, 685–687.CrossRefGoogle Scholar
Allocca, M., Doria, M., Petrillo, M., Colella, P., Garcia-Hoyos, M., Gibbs, D., Kim, S.R., Maguire, A., Rex, T.S., Di Vicino, U., Cutillo, L., Sparrow, J.R., Williams, D.S., Bennett, J. & Auricchio, A. (2008). Serotype-dependent packaging of large genes in adeno-associated viral vectors results in effective gene delivery in mice. The Journal of Clinical Investigation 118, 1955–1964.Google Scholar
Amado, D., Mingozzi, F., Hui, D., Bennicelli, J.L., Wei, Z., Chen, Y., Bote, E., Grant, R.L., Golden, J.A., Narfstrom, K., Syed, N.A., Orlin, S.E., High, K.A., Maguire, A.M. & Bennett, J. (2010). Safety and efficacy of subretinal readministration of a viral vector in large animals to treat congenital blindness. Science Translational Medicine 2, 21ra16.CrossRefGoogle ScholarPubMed
Ames, A. 3rd. (2000). CNS energy metabolism as related to function. Brain Research Reviews 34, 42–68.CrossRefGoogle ScholarPubMed
Annear, M.J., Bartoe, J.T., Barker, S.E., Smith, A.J., Curran, P.G., Bainbridge, J.W., Ali, R.R., Petersen-Jones, S.M. (2011). Gene therapy in the second eye of RPE65-deficient dogs improves retinal function. Gene Therapy 18, 53–61.CrossRefGoogle ScholarPubMed
Athanasiou, D., Aguilà, M., Bevilacqua, D., Novoselov, S.S., Parfitt, D.A. & Cheetham, M.E. (2013). The cell stress machinery and retinal degeneration. FEBS Letters 587, 2008–2017.Google Scholar
Bainbridge, J.W., Smith, A.J., Barker, S.S., Robbie, S., Henderson, R., Balaggan, K., Viswanathan, A., Holder, G.E., Stockman, A., Tyler, N., Petersen-Jones, S., Bhattacharya, S.S., Thrasher, A.J., Fitzke, F.W., Carter, B.J., Rubin, G.S., Moore, A.T. & Ali, R.R. (2008). Effect of gene therapy on visual function in Leber's congenital amaurosis. The New England Journal of Medicine 358, 2231–2239.CrossRefGoogle ScholarPubMed
Bainbridge, J.W., Tan, M.H. & Ali, R.R. (2006). Gene therapy progress and prospects: The eye. Gene Therapy 13, 1191–1197.Google Scholar
Barot, M., Gokulgandhi, M.R. & Mitra, A.K. (2011). Mitochondrial dysfunction in retinal diseases. Current Eye Research 36, 1069–1077.Google Scholar
Bartel, M.A., Weinstein, J.R. & Schaffer, D.V. (2012). Directed evolution of novel adeno-associated viruses for therapeutic gene delivery. Gene Therapy 19, 694–700.Google Scholar
Batten, M.L., Imanishi, Y., Tu, D.C., Doan, T., Zhu, L., Pang, J., Glushakova, L., Moise, A.R., Baehr, W., Van Gelder, R.N., Hauswirth, W.W., Rieke, F. & Palczewski, K. (2005). Pharmacological and rAAV gene therapy rescue of visual functions in a blind mouse model of Leber congenital amaurosis. PLoS Medicine 2, e333.CrossRefGoogle Scholar
Baye, L.M., Patrinostro, X., Swaminathan, S., Beck, J.S., Zhang, Y., Stone, E.M., Sheffield, V.C. & Slusarski, D.C. (2011). The N-terminal region of centrosomal protein 290 (CEP290) restores vision in a zebrafish model of human blindness. Human Molecular Genetics 20, 1467–1477.Google Scholar
Beltran, W.A., Cideciyan, A.V., Lewin, A.S., Iwabe, S., Khanna, H., Sumaroka, A., Chiodo, V.A., Fajardo, D.S., Román, A.J., Deng, W.T., Swider, M., Alemán, T.S., Boye, S.L., Genini, S., Swaroop, A., Hauswirth, W.W., Jacobson, S.G. & Aguirre, G.D. (2012). Gene therapy rescues photoreceptor blindness in dogs and paves the way for treating human X-linked retinitis pigmentosa. Proceedings of the National Academy of Sciences of the United States of America 109, 2132–2137.CrossRefGoogle ScholarPubMed
Bennett, J., Ashtari, M., Wellman, J., Marshall, K.A., Cyckowski, L.L., Chung, D.C., McCague, S., Pierce, E.A., Chen, Y., Bennicelli, J.L., Zhu, X., Ying, G.S., Sun, J., Wright, J.F., Auricchio, A., Simonelli, F., Shindler, K.S., Mingozzi, F., High, K.A. & Maguire, A.M. (2012). AAV2 gene therapy readministration in three adults with congenital blindness. Science Translational Medicine 4, 120ra15.CrossRefGoogle ScholarPubMed
Bennicelli, J., Wright, J.F., Komaromy, A., Jacobs, J.B., Hauck, B., Zelenaia, O., Mingozzi, F., Hui, D., Chung, D., Rex, T.S., Wei, Z., Qu, G., Zhou, S., Zeiss, C., Arruda, V.R., Acland, G.M., Dell'Osso, L.F., High, K.A., Maguire, A.M. & Bennett, J. (2008). Reversal of blindness in animal models of Leber congenital amaurosis using optimized AAV2-mediated gene transfer. Molecular Therapy 16, 458–465.Google Scholar
Bhattacharya, S.S., Wright, A.F., Clayton, J.F., Price, W.H., Phillips, C.I., McKeown, C.M., Jay, M., Bird, A.C., Pearson, P.L. & Southern, E.M. (1984). Close genetic linkage between X-linked retinitis pigmentosa and a restriction fragment length polymorphism identified by recombinant DNA probe L1.28. Nature 309, 253–255.CrossRefGoogle Scholar
Bi, A., Cui, J., Ma, Y.P., Olshevskaya, E., Pu, M., Dizhoor, A.M. & Pan, Z.H. (2006). Ectopic expression of a microbial-type rhodopsin restores visual responses in mice with photoreceptor degeneration. Neuron 50, 23–33.CrossRefGoogle ScholarPubMed
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, K.A. (2013). Transduction of photoreceptors with equine infectious anemia virus lentiviral vectors: Safety and biodistribution of StarGen for Stargardt disease. Investigative Ophthalmology Visual Science 54, 4061–4071.CrossRefGoogle ScholarPubMed
Binley, K., Widdowson, P.S., Kelleher, M., de Belin, J., Loader, J., Ferrige, G., Carlucci, M., Esapa, M., Chipchase, D., Angell-Manning, D., Ellis, S., Mitrophanous, K., Miskin, J., Bantseev, V., Nork, T.M., Miller, P. & Naylor, S. (2012). Safety and biodistribution of an equine infectious anemia virus-based gene therapy, RetinoStat(®), for age-related macular degeneration. Human Gene Therapy 23, 980–991.Google Scholar
Birch, D.G., Weleber, R.G., Duncan, J.L., Jaffe, G.J. & Tao, W. (2013). Ciliary neurotrophic factor retinitis pigmentosa study groups. Randomized trial of ciliary neurotrophic factor delivered by encapsulated cell intraocular implants for retinitis pigmentosa. American Journal Ophthalmology 156, 283–292.e1.Google Scholar
Bonnet, C., Augustin, S., Ellouze, S., Bénit, P., Bouaita, A., Rustin, P., Sahel, J.A. & Corral-Debrinski, M. (2008). The optimized allotopic expression of ND1 or ND4 genes restores respiratory chain complex I activity in fibroblasts harboring mutations in these genes. Biochimica et Biophysica Acta 1783, 1707–1717.Google Scholar
Boucherie, C., Sowden, J.C. & Ali, R.R. (2011). Induced pluripotent stem cell technology for generating photoreceptors. Regenerative Medicine 6, 469–479.Google Scholar
Boye, S.E., Boye, S.L., Pang, J., Ryals, R., Everhart, D., Umino, Y., Neeley, A.W., Besharse, J., Barlow, R. & Hauswirth, W.W. (2010). Functional and behavioral restoration of vision by gene therapy in the guanylate cyclase-1 (GC1) knockout mouse. PLoS One 5, e11306.Google Scholar
Boye, S.L., Conlon, T., Erger, K., Ryals, R., Neeley, A., Cossette, T., Pang, J., Dyka, F.M., Hauswirth, W.W. & Boye, S.E. (2011). Long-term preservation of cone photoreceptors and restoration of cone function by gene therapy in the guanylate cyclase-1 knockout (GC1KO) mouse. Investigative Ophthalmology & Visual Science 52, 7098–7108.Google Scholar
Boye, S.E., Boye, S.L., Lewin, A.S. & Hauswirth, W.W. (2013a). A comprehensive review of retinal gene therapy. Molecular Therapy 21, 509–519.Google Scholar
Boye, S.L., Peshenko, I.V., Huang, W.C., Min, S.H., McDoom, I., Kay, C.N., Liu, X., Dyka, F.M., Foster, T.C., Umino, Y., Karan, S., Jacobson, S.G., Baehr, W., Dizhoor, A., Hauswirth, W.W. & Boye, S.E. (2013b). AAV-mediated gene therapy in the guanylate cyclase (RetGC1/RetGC2) double knockout mouse model of Leber congenital amaurosis. Human Gene Therapy 24, 189–202.Google Scholar
Buch, P.K., MacLaren, R.E., Durán, Y., Balaggan, K.S., MacNeil, A., Schlichtenbrede, F.C., Smith, A.J. & Ali, R.R. (2006). In contrast to AAV-mediated Cntf expression, AAV-mediated Gdnf expression enhances gene replacement therapy in rodent models of retinal degeneration. Molecular Therapy 14, 700–709.CrossRefGoogle ScholarPubMed
Bunting, M., Bernstein, K.E., Greer, J.M., Capecchi, M.R. & Thomas, K.R. (1999). Targeting genes for self-excision in the germ line. Genes & Development 13, 1524–1528.Google Scholar
Busskamp, V., Duebel, J., Balya, D., Fradot, M., Viney, T.J., Siegert, S., Groner, A.C., Cabuy, E., Forster, V., Seeliger, M., Biel, M., Humphries, P., Paques, M., Mohand-Said, S., Trono, D., Deisseroth, K., Sahel, J.A., Picaud, S. & Roska, B. (2010). Genetic reactivation of cone photoreceptors restores visual responses in retinitis pigmentosa. Science 329, 413–417.Google Scholar
Busskamp, V., Picaud, S., Sahel, J.A. & Roska, B. (2012). Optogenetic therapy for retinitis pigmentosa. Gene Therapy 19, 169–175.Google Scholar
Byrne, L.C., Khalid, F., Lee, T., Zin, E.A., Greenberg, K.P., Visel, M., Schaffer, D.V., Flannery, J.G. (2013). AAV-mediated, optogenetic ablation of Müller glia leads to structural and functional changes in the mouse retina. PLoS One 8, e76075.Google Scholar
Cai, X., Conley, S.M., Nash, Z., Fliesler, S.J., Cooper, M.J. & Naash, M.I. (2010). Gene delivery to mitotic and postmitotic photoreceptors via compacted DNA nanoparticles results in improved phenotype in a mouse model of retinitis pigmentosa. FASEB Journal 24, 1178–1191.Google Scholar
Caporale, N., Kolstad, K.D., Lee, T., Tochitsky, I., Dalkara, D., Trauner, D., Kramer, R., Dan, Y., Isacoff, E.Y. & Flannery, J.G. (2011). LiGluR restores visual responses in rodent models of inherited blindness. Molecular Therapy 19, 1212–1219.CrossRefGoogle ScholarPubMed
Carvalho, L.S., Xu, J., Pearson, R.A., Smith, A.J., Bainbridge, J.W., Morris, L.M., Fliesler, S.J., Ding, X.Q. & Ali, R.R. (2011). Long-term and age-dependent restoration of visual function in a mouse model of CNGB3-associated achromatopsia following gene therapy. Human Molecular Genetics 20, 3161–3175.Google Scholar
Castel, S.E. & Martienssen, R.A. (2013). RNA interference in the nucleus: Roles for small RNAs in transcription, epigenetics and beyond. Nature Reviews Genetics 14, 100–112.Google Scholar
Chadderton, N., Millington-Ward, S., Palfi, A., O'Reilly, M., Tuohy, G., Humphries, M.M., Li, T., Humphries, P., Kenna, P.F. & Farrar, G.J. (2009). Improved retinal function in a mouse model of dominant retinitis pigmentosa following AAV-delivered gene therapy. Molecular Therapy 17, 593–599.Google Scholar
Chadderton, N., Palfi, A., Millington-Ward, S., Gobbo, O., Overlack, N., Carrigan, M., O'Reilly, M., Campbell, M., Ehrhardt, C., Wolfrum, U., Humphries, P., Kenna, P.F. & Jane Farrar, G. (2013). Intravitreal delivery of AAV-NDI1 provides functional benefit in a murine model of Leber hereditary optic neuropathy. European Journal of Human Genetics 21, 62–68.CrossRefGoogle Scholar
Chang, B., Dacey, M.S., Hawes, N.L., Hitchcock, P.F., Milam, A.H., Atmaca-Sonmez, P., Nusinowitz, S. & Heckenlively, J.R. (2006). Cone photoreceptor function loss-3, a novel mouse model of achromatopsia due to a mutation in Gnat2. Investigative Ophthalmology & Visual Science 47, 5017–5021.Google Scholar
Charbel, I.P. & MacLaren, R.E. (2012). Non-viral retinal gene therapy: A review. Clinical & Experimental Ophthalmology 40, 39–47.Google Scholar
Cideciyan, A.V. (2010). Leber congenital amaurosis due to RPE65 mutations and its treatment with gene therapy. Progress in Retinal and Eye Research Sep;29(5):398–427.Google Scholar
Cideciyan, A.V., Aleman, T.S., Boye, S.L., Schwartz, S.B., Kaushal, S., Roman, A.J., Pang, J.J., Sumaroka, A., Windsor, E.A., Wilson, J.M., Flotte, T.R., Fishman, G.A., Heon, E., Stone, E.M., Byrne, B.J., Jacobson, S.G. & Hauswirth, W.W. (2008 Sept 30). Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics. Proceedings of the National Academy of Sciences of the United States of America 105, 15112–15117.CrossRefGoogle Scholar
Cideciyan, A.V., Jacobson, S.G., Beltran, W.A., Sumaroka, A., Swider, M., Iwabe, S., Roman, A.J., Olivares, M.B., Schwartz, S.B., Komáromy, A.M., Hauswirth, W.W. & Aguirre, G.D. (2013). Human retinal gene therapy for Leber congenital amaurosis shows advancing retinal degeneration despite enduring visual improvement. Proceedings of the National Academy of Sciences of the United States of America 110, E517–E525.Google Scholar
Colella, P., Sommella, A., Marrocco, E., Di Vicino, U., Polishchuk, E., Garrido, M.G., Seeliger, M.W., Polishchuk, R. & Auricchio, A. (2013). Myosin7a deficiency results in reduced retinal activity which is improved by gene therapy. PLoS One 8, e72027.Google Scholar
Collin, R.W., den Hollander, A.I., van der Velde-Visser, S.D., Bennicelli, J., Bennett, J. & Cremers, F.P. (2012). Antisense Oligonucleotide (AON)-based therapy for Leber congenital amaurosis caused by a frequent mutation in CEP290. Molecular Therapy Nucleic Acids 1, e14.Google Scholar
Conlon, T.J., Deng, W.T., Erger, K., Cossette, T., Pang, J.J., Ryals, R., Clément, N., Cleaver, B., McDoom, I., Boye, S.E., Peden, M.C., Sherwood, M.B., Abernathy, C.R., Alkuraya, F.S., Boye, S.L. & Hauswirth, W.W. (2013). Preclinical potency and safety studies of an AAV2-mediated gene therapy vector for the treatment of MERTK associated retinitis pigmentosa. Human Gene Therapy Clinical Development 24, 23–28.Google Scholar
Curtis, R., Barnett, K.C. & Leon, A. (1987). An early-onset retinal dystrophy with dominant inheritance in the Abyssinian cat. Clinical and pathological findings. Investigative Ophthalmology & Visual Science 28, 131–139.Google Scholar
Dalkara, D., Byrne, L.C., Klimczak, R.R., Visel, M., Yin, L., Merigan, W.H., Flannery, J.G. & Schaffer, D.V. (2013). In vivo-directed evolution of a new adeno-associated virus for therapeutic outer retinal gene delivery from the vitreous. Science Translational Medicine 5, 189ra76.CrossRefGoogle ScholarPubMed
Dalkara, D., Byrne, L.C., Lee, T., Hoffmann, N.V., Schaffer, D.V. & Flannery, J.G. (2012). Enhanced gene delivery to the neonatal retina through systemic administration of tyrosine-mutated AAV9. Gene Therapy Feb;19(2):176–181.Google Scholar
Dalkara, D., Kolstad, K.D., Guerin, K.I., Hoffmann, N.V., Visel, M., Klimczak, R.R., Schaffer, D.V. & Flannery, J.G. (2011). AAV mediated GDNF secretion from retinal glia slows down retinal degeneration in a rat model of retinitis pigmentosa. Molecular Therapy 19, 1602–1608.Google Scholar
Davis, R.J., Hsu, C.-W., Tsai, Y.-T., Wert, K.J., Sancho-Pelluz, J., Lin, C.-S., Tsang, S.H. (2013). Therapeutic margins in a novel preclinical model of retinitis pigmentosa. Journal of Neuroscience 33, 13475–13483.Google Scholar
Davis, R.J., Tosi, J., Janisch, K.M., Kasanuki, J.M., Wang, N.K., Kong, J., Tsui, I., Cilluffo, M., Woodruff, M.L., Fain, G.L., Lin, C.S. & Tsang, S.H. (2008). Functional rescue of degenerating photoreceptors in mice homozygous for a hypomorphic cGMP phosphodiesterase 6 b allele (Pde6bH620Q). Investigative Ophthalmology & Visual Science 49, 5067–5076.Google Scholar
Dinculescu, A., Estreicher, J., Zenteno, J.C., Aleman, T.S., Schwartz, S.B., Huang, W.C., Roman, A.J., Sumaroka, A., Li, Q., Deng, W.-T., Min, S.-H., Chiodo, V.A., Neeley, A., Liu, X., Shu, X., Matias-Florentino, M., Buentello-Volante, B., Boye, S.L., Cideciyan, A.V., Hauswirth, W.W. & Jacobson, S.G. (2011). Gene therapy for retinitis pigmentosa caused by MFRP mutations: Human phenotype and preliminary proof of concept. Human Gene Therapy 23, 367–376.Google Scholar
Doonan, F., Donovan, M. & Cotter, T.G. (2003). Caspase-independent photoreceptor apoptosis in mouse models of retinal degeneration. Journal of Neuroscience 23, 5723–5731.Google Scholar
Doonan, F., Groeger, G. & Cotter, T.G. (2012). Preventing retinal apoptosis – Is there a common therapeutic theme? Experimental Cell Research 318, 1278–1284.Google Scholar
Doroudchi, M.M., Greenberg, K.P., Liu, J., Silka, K.A., Boyden, E.S., Lockridge, J.A., Arman, A.C., Janani, R., Boye, S.E., Boye, S.L., Gordon, G.M., Matteo, B.C., Sampath, A.P., Hauswirth, W.W. & Horsager, A. (2011). Virally delivered channelrhodopsin-2 safely and effectively restores visual function in multiple mouse models of blindness. Molecular Therapy 19, 1220–1229.CrossRefGoogle ScholarPubMed
Duan, D., Yue, Y., Engelhardt, J.F. (2001). Expanding AAV packaging capacity with trans-splicing or overlapping vectors: A quantitative comparison. Molecular Therapy 4, 383–391.Google Scholar
Elbashir, S.M., Harborth, J., Lendeckel, W., Yalcin, A., Weber, K. & Tuschl, T. (2001). Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411, 494–498.Google Scholar
Ellouze, S., Augustin, S., Bouaita, A., Bonnet, C., Simonutti, M., Forster, V., Picaud, S., Sahel, J.A. & Corral-Debrinski, M. (2008). Optimized allotopic expression of the human mitochondrial ND4 prevents blindness in a rat model of mitochondrial dysfunction. American Journal of Human Genetics 83, 373–387.Google Scholar
Estrada-Cuzcano, A., Roepman, R., Cremers, F.P., den Hollander, A.I. & Mans, D.A. (2012). Non-syndromic retinal ciliopathies: Translating gene discovery into therapy. Human Molecular Genetics 21, R111–R124.Google Scholar
Farrar, G.J., Chadderton, N., Kenna, P.F. & Millington-Ward, S. (2013). Mitochondrial disorders: Aetiologies, models systems, and candidate therapies. Trends in Genetics 29, 488–497.Google Scholar
Farrar, G.J., Millington-Ward, S., Chadderton, N., Humphries, P. & Kenna, P.F. (2012). Gene-based therapies for dominantly inherited retinopathies. Gene Therapy 19, 137–144.Google Scholar
Fire, A., Xu, S., Montgomery, M.K., Kostas, S.A., Driver, S.E. & Mello, C.C. (1998). Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391, 806–811.Google Scholar
Flannery, J.G. & Visel, M. (2013). Adeno-associated viral vectors for gene therapy of inherited retinal degenerations. Methods in Molecular Biology 935, 351–369.Google Scholar
Fletcher, E.L., Jobling, A.I., Vessey, K.A., Luu, C., Guymer, R.H. & Baird, P.N. (2011). Animal models of retinal disease. Progress in Molecular Biology and Translational Science 100, 211–286.Google Scholar
Fridlich, R., Delalande, F., Jaillard, C., Lu, J., Poidevin, L., Cronin, T., Perrocheau, L., Millet-Puel, G., Niepon, M.L., Poch, O., Holmgren, A., Van Dorsselaer, A., Sahel, J.A. & Léveillard, T. (2009). The thioredoxin-like protein rod-derived cone viability factor (RdCVFL) interacts with TAU and inhibits its phosphorylation in the retina. Molecular & Cellular Proteomics 8, 1206–1218.Google Scholar
Gaj, T., Gersbach, C.A. & Barbas, C.F. 3rd. (2013). ZFN, TALEN, and CRISPR/Cas-based methods for genome engineering. Trends in Biotechnology 31, 397–405.Google Scholar
Gargiulo, A., Bonetti, C., Montefusco, S., Neglia, S., Di Vicino, U., Marrocco, E., Corte, M.D., Domenici, L., Auricchio, A. & Surace, E.M. (2009). AAV-mediated tyrosinase gene transfer restores melanogenesis and retinal function in a model of oculo-cutaneous albinism type I (OCA1). Molecular Therapy 17, 1347–1354.Google Scholar
Georgiadis, A., Tschernutter, M., Bainbridge, J.W., Robbie, S.J., McIntosh, J., Nathwani, A.C., Smith, A.J. & Ali, R.R. (2010). AAV-mediated knockdown of peripherin-2 in vivo using miRNA-based hairpins. Gene Therapy 17, 486–493.Google Scholar
Gorbatyuk, M., Justilien, V., Liu, J., Hauswirth, W.W. & Lewin, A.S. (2007). Preservation of photoreceptor morphology and function in P23H rats using an allele independent ribozyme. Experimental Eye Research 84, 44–52.Google Scholar
Gorbatyuk, M.S., Knox, T., LaVail, M.M., Gorbatyuk, O.S., Noorwez, S.M., Hauswirth, W.W., Lin, J.H., Muzyczka, N. & Lewin, A.S. (2010). Restoration of visual function in P23H rhodopsin transgenic rats by gene delivery of BiP/Grp78. Proceedings of the National Academy of Sciences of the United States of America 107, 5961–5966.Google Scholar
Gorbatyuk, M.S., Pang, J.J., Thomas, J. Jr., Hauswirth, W.W. & Lewin, A.S. (2005). Knockdown of wild-type mouse rhodopsin using an AAV vectored ribozyme as part of an RNA replacement approach. Molecular Vision 11, 648–656.Google Scholar
Greenwald, D.L., Cashman, S.M. & Kumar-Singh, R. (2013). Mutation-independent rescue of a novel mouse model of retinitis pigmentosa. Gene Therapy 20, 425–434.Google Scholar
Griciuc, A., Aron, L. & Ueffing, M. (2011). ER stress in retinal degeneration: A target for rational therapy? Trends in Molecular Medicine 17, 442–451.Google Scholar
Gurtan, A.M. & Sharp, P.A. (2013). The role of miRNAs in regulating gene expression networks. Journal of Molecular Biology 425, 3582–3600.Google Scholar
Guy, J., Qi, X., Koilkonda, R.D., Arguello, T., Chou, T.H., Ruggeri, M., Porciatti, V., Lewin, A.S. & Hauswirth, W.W. (2009). Efficiency and safety of AAV-mediated gene delivery of the human ND4 complex I subunit in the mouse visual system. Investigative Ophthalmology & Visual Science 50, 4205–4214.Google Scholar
Guziewicz, K.E., Zangerl, B., Komáromy, A.M., Iwabe, S., Chiodo, V.A., Boye, S.L., Hauswirth, W.W., Beltran, W.A. & Aguirre, G.D. (2013). Recombinant AAV-mediated BEST1 transfer to the retinal pigment epithelium: Analysis of serotype-dependent retinal effects. PLoS One 8, e75666.Google Scholar
Han, Z., Conley, S.M., Makkia, R.S., Cooper, M.J. & Naash, M.I. (2012). DNA nanoparticle-mediated ABCA4 delivery rescues Stargardt dystrophy in mice. The Journal of Clinical Investigation 122, 3221–3226.Google Scholar
Hao, W., Wenzel, A., Obin, M.S., Chen, C.K., Brill, E., Krasnoperova, N.V., Eversole-Cire, P., Kleyner, Y., Taylor, A., Simon, M.I., Grimm, C., Remé, C.E. & Lem, J. (2002). Evidence for two apoptotic pathways in light-induced retinal degeneration. Nature Genetics 232, 254–260.Google Scholar
Hashimoto, T., Gibbs, D., Lillo, C., Azarian, S.M., Legacki, E., Zhang, X.M., Yang, X.J. & Williams, D.S. (2007). Lentiviral gene replacement therapy of retinas in a mouse model for Usher syndrome type 1B. Gene Therapy 14, 584–594.Google Scholar
Hauswirth, W.W., Aleman, T.S., Kaushal, S., Cideciyan, A.V., Schwartz, S.B., Wang, L., Conlon, T.J., Boye, S.L., Flotte, T.R., Byrne, B.J. & Jacobson, S.G. (2008). Treatment of leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial. Human Gene Therapy Oct;19(10): 979–990.Google Scholar
Humphries, M.M., Rancourt, D., Farrar, G.J., Kenna, P., Hazel, M., Bush, R.A., Sieving, P.A., Sheils, D.M., McNally, N., Creighton, P., Erven, A., Boros, A., Gulya, K., Capecchi, M.R. & Humphries, P. (1997). Retinopathy induced in mice by targeted disruption of the rhodopsin gene. Nature Genetics 15, 216–219.Google Scholar
Jacobson, S.G., Acland, G.M., Aguirre, G.D., Aleman, T.S., Schwartz, S.B., Cideciyan, A.V., Zeiss, C.J., Komaromy, A.M., Kaushal, S., Roman, A.J., Windsor, E.A., Sumaroka, A., Pearce-Kelling, S.E., Conlon, T.J., Chiodo, V.A., Boye, S.L., Flotte, T.R., Maguire, A.M., Bennett, J. & Hauswirth, W.W. (2006). Safety of recombinant adeno-associated virus type 2-RPE65 vector delivered by ocular subretinal injection. Molecular Therapy 13, 1074–1084.Google Scholar
Jaillard, C., Mouret, A., Niepon, M.L., Clérin, E., Yang, Y., Lee-Rivera, I., Aït-Ali, N., Millet-Puel, G., Cronin, T., Sedmak, T., Raffelsberger, W., Kinzel, B., Trembleau, A., Poch, O, Bennett, J., Wolfrum, U., Lledo, P.M., Sahel, J.A., Léveillard, T. (2012). Nxnl2 splicing results in dual functions in neuronal cell survival and maintenance of cell integrity. Human Molecular Genetics 21, 2298–2311.Google Scholar
Janssen, A., Min, S.H., Molday, L.L., Tanimoto, N., Seeliger, M.W., Hauswirth, W.W., Molday, R.S. & Weber, B.H. (2008). Effect of late-stage therapy on disease progression in AAV-mediated rescue of photoreceptor cells in the retinoschisin-deficient mouse. Molecular Therapy 16, 1010–1017.Google Scholar
Keiser, M.S., Geoghegan, J.C., Boudreau, R.L., Lennox, K.A. & Davidson, B.L. (2013). RNAi or overexpression: Alternative therapies for spinocerebellar ataxia type 1. Neurobiology of Disease 56, 6–13.Google Scholar
Kjellstrom, S., Bush, R.A., Zeng, Y., Takada, Y., Sieving, P.A. (2007). Retinoschisin gene therapy and natural history in the Rs1h-KO mouse: Long-term rescue from retinal degeneration. Investigative Ophthalmology & Visual Science 48, 3837–3845.Google Scholar
Koch, S., Sothilingam, V., Garcia Garrido, M., Tanimoto, N., Becirovic, E., Koch, F., Seide, C., Beck, S.C., Seeliger, M.W., Biel, M., Mühlfriedel, R. & Michalakis, S. (2012). Gene therapy restores vision and delays degeneration in the CNGB1(-/-) mouse model of retinitis pigmentosa. Human Molecular Genetics 21, 4486–4496.CrossRefGoogle ScholarPubMed
Koilkonda, R.D., Chou, T.H., Porciatti, V., Hauswirth, W.W. & Guy, J. (2010). Induction of rapid and highly efficient expression of the human ND4 complex I subunit in the mouse visual system by self-complementary adeno-associated virus. Archives of Ophthalmology 128, 876–883.Google Scholar
Komáromy, A.M., Alexander, J.J., Rowlan, J.S., Garcia, M.M., Chiodo, V.A., Kaya, A., Tanaka, J.C., Acland, G.M., Hauswirth, W.W. & Aguirre, G.D. (2010). Gene therapy rescues cone function in congenital achromatopsia. Human Molecular Genetics 19, 2581–2593.Google Scholar
Komáromy, A.M., Rowlan, J.S., Corr, A.T., Reinstein, S.L., Boye, S.L., Cooper, A.E., Gonzalez, A., Levy, B., Wen, R., Hauswirth, W.W., Beltran, W.A. & Aguirre, G.D. (2013). Transient photoreceptor deconstruction by CNTF enhances rAAV-mediated cone functional rescue in late stage CNGB3-achromatopsia. Molecular Therapy 21, 1131–1141.Google Scholar
Komeima, K., Rogers, B.S. & Campochiaro, P.A. (2007). Antioxidants slow photoreceptor cell death in mouse models of retinitis pigmentosa. Journal of Cellular Physiology 213, 809–815.Google Scholar
Kong, J., Kim, S.R., Binley, K., Pata, I., Doi, K., Mannik, J., Zernant-Rajang, J., Kan, O., Iqball, S., Naylor, S., Sparrow, J.R., Gouras, P. & Allikmets, R. (2008). Correction of the disease phenotype in the mouse model of Stargardt disease by lentiviral gene therapy. Gene Therapy 15, 1311–1320.CrossRefGoogle ScholarPubMed
Kong, L., Zhou, X., Li, F., Yodoi, J., McGinnis, J. & Cao, W. (2010). Neuroprotective effect of overexpression of thioredoxin on photoreceptor degeneration in tubby mice. Neurobiology of Disease 38, 446–455.CrossRefGoogle ScholarPubMed
Ku, C.A., Chiodo, V.A., Boye, S.L., Goldberg, A.F., Li, T., Hauswirth, W.W. & Ramamurthy, V. (2011). Gene therapy using self-complementary Y733F capsid mutant AAV2/8 restores vision in a model of early onset Leber congenital amaurosis. Human Molecular Genetics 20, 4569–4581.Google Scholar
Lam, B.L., Feuer, W.J., Abukhalil, F., Porciatti, V., Hauswirth, W.W. & Guy, J. (2010). Leber hereditary optic neuropathy gene therapy clinical trial recruitment: Year 1. Archives of Ophthalmology 128, 1129–1135.Google Scholar
LaVail, M.M., Yasumura, D., Matthes, M.T., Drenser, K.A., Flannery, J.G., Lewin, A.S. & Hauswirth, W.W. (2000). Ribozyme rescue of photoreceptor cells in P23H transgenic rats: Long-term survival and late-stage therapy. Proceedings of the National Academy of Sciences of the United States of America 97, 11488–11493.Google Scholar
Leaver, S.G., Cui, Q., Bernard, O. & Harvey, A.R. (2006). Cooperative effects of bcl-2 and AAV-mediated expression of CNTF on retinal ganglion cell survival and axonal regeneration in adult transgenic mice. European Journal of Neuroscience 24, 3323–3332.Google Scholar
Lem, J., Krasnoperova, N.V., Calvert, P.D., Kosaras, B., Cameron, D.A., Nicolò, M., Makino, C.L. & Sidman, R.L. (1999). Morphological, physiological, and biochemical changes in rhodopsin knockout mice. Proceedings of the National Academy of Sciences of the United States of America 96, 736–741.Google Scholar
Le Meur, G., Stieger, K., Smith, A.J., Weber, M., Deschamps, J.Y., Nivard, D., Mendes-Madeira, A., Provost, N., Péréon, Y., Cherel, Y., Ali, R.R., 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 Therapy 14, 292–303.CrossRefGoogle ScholarPubMed
Leonard, K.C., Petrin, D., Coupland, S.G., Baker, A.N., Leonard, B.C., LaCasse, E.C., Hauswirth, W.W., Korneluk, R.G., Tsilfidis, C. (2007). XIAP protection of photoreceptors in animal models of retinitis pigmentosa. PLoS One 2, e314.Google Scholar
Léveillard, T., Mohand-Saïd, S., Lorentz, O., Hicks, D., Fintz, A.C., E., Simonutti, M., Forster, V., Cavusoglu, N., Chalmel, F., Dollé, P., Poch, O., Lambrou, G. & Sahel, J.A. (2004). Identification and characterization of rod-derived cone viability factor. Nature Genetics Jul;36(7):755–759.Google Scholar
Léveillard, T. & Sahel, J.A. (2010). Rod-derived cone viability factor for treating blinding diseases: From clinic to redox signaling. Science Translational Medicine 2, 26ps16.Google Scholar
Lewin, A.S., Drenser, K.A., Hauswirth, W.W., Nishikawa, S., Yasumura, D., Flannery, J.G. & LaVail, M.M. (1998). Ribozyme rescue of photoreceptor cells in a transgenic rat model of autosomal dominant retinitis pigmentosa. Nature Medicine 4, 967–971. Erratum in: Nature Medicine, 1998, 4(9): 1081.Google Scholar
Li, L.C. (2014). Chromatin remodeling by the small RNA machinery in mammalian cells. Epigenetics 9, 45–52.Google Scholar
Lin, B., Koizumi, A., Tanaka, N., Panda, S., Masland, R.H. (2008). Restoration of visual function in retinal degeneration mice by ectopic expression of melanopsin. Proceedings of the National Academy of Sciences of the United States of America 105, 16009–16014.Google Scholar
Lhériteau, E., Petit, L., Weber, M., Le Meur, G., Deschamps, J.Y., Libeau, L., Mendes-Madeira, A., Guihal, C., François, A., Guyon, R., Provost, N., Lemoine, F., Papal, S., El-Amraoui, A., Colle, M.A., Moullier, P. & Rolling, F. (2013). Successful gene therapy in the RPGRIP1-deficient dog: A large model of cone-rod dystrophy. Molecular Therapy Doi: 10.1038/mt.2013.232.Google Scholar
Lopes, V.S., Boye, S.E., Louie, C.M., Boye, S., Dyka, F., Chiodo, V., Fofo, H., Hauswirth, W.W., Williams, D.S. (2013). Retinal gene therapy with a large MYO7A cDNA using adeno-associated virus. Gene Therapy 20, 824–833.Google Scholar
MacLaren, R.E., Groppe, M., Barnard, A.R., Cottrial, C.L., Tolmachova, T., Seymour, L., Clark, K.R., During, M.J., Cremers, F.P.M., Black, G.C.M., Lotery, A.J., Downes, S.M., Webster, A.R. & Seabra, M.C. (2014). Retinal gene therapy in patients with choroideremia: Initial findings from a phase I/II clinical trail. The Lancet, online publication Jan 16, 2014, http://dx.doi.org/10.1016/S0140-6736(13)62117-0Google Scholar
Maguire, A.M., Simonelli, F., Pierce, E.A., Pugh, E.N. Jr., Mingozzi, F., Bennicelli, J., Banfi, S., Marshall, K.A., Testa, F., Surace, E.M., Rossi, S., Lyubarsky, A., Arruda, V.R., Konkle, B., Stone, E., Sun, J., Jacobs, J., Dell'Osso, L., Hertle, R., Ma, J.X., Redmond, T.M., Zhu, X., Hauck, B., Zelenaia, O., Shindler, K.S., Maguire, M.G., Wright, J.F., Volpe, N.J., McDonnell, J.W., Auricchio, A., High, K.A. & Bennett, J. (2008 May 22). Safety and efficacy of gene transfer for Leber's congenital amaurosis. New England Journal of Medicine 358, 2240–2248.Google Scholar
Mao, H., Gorbatyuk, M.S., Rossmiller, B., Hauswirth, W.W., Lewin, A.S. (2012). Long-term rescue of retinal structure and function by rhodopsin RNA replacement with a single adeno-associated viral vector in P23H RHO transgenic mice. Human Gene Therapy 23, 356–366.Google Scholar
Mao, H., James, T. Jr., Schwein, A., Shabashvili, A.E., Hauswirth, W.W., Gorbatyuk, M.S. & Lewin, A.S. (2011). AAV delivery of wild-type rhodopsin preserves retinal function in a mouse model of autosomal dominant retinitis pigmentosa. Human Gene Therapy 22, 567–575.Google Scholar
Marella, M., Seo, B.B., Thomas, B.B., Matsuno-Yagi, A. & Yagi, T.(2010). Successful amelioration of mitochondrial optic neuropathy using the yeast NDI1 gene in a rat animal model. PLoS One 5, e11472.Google Scholar
Marigo, V (2007). Programmed cell death in retinal degeneration: Targeting apoptosis in photoreceptors as potential therapy for retinal degeneration. Cell Cycle 16, 652–655.Google Scholar
Menotti-Raymond, M., Deckman, K.H., David, V., Myrkalo, J., O’Brien, S.J., Narfström, K. (2010). Mutation discovered in a feline model of human congenital retinal blinding disease. Investigative Ophthalmology & Visual Science 51, 2852–2859.Google Scholar
Michalakis, S., Mühlfriedel, R., Tanimoto, N., Krishnamoorthy, V., Koch, S., Fischer, M.D., Becirovic, E., Bai, L., Huber, G., Beck, S.C., Fahl, E., Büning, H., Paquet-Durand, F., Zong, X., Gollisch, T., Biel, M. & Seeliger, M.W. (2010). Restoration of cone vision in the CNGA3-/- mouse model of congenital complete lack of cone photoreceptor function. Molecular Therapy 18, 2057–2063.Google Scholar
Michalakis, S., Mühlfriedel, R., Tanimoto, N., Krishnamoorthy, V., Koch, S., Fischer, M.D., Becirovic, E., Bai, L., Huber, G., Beck, S.C., Fahl, E., Büning, H., Schmidt, J., Zong, X., Gollisch, T., Biel, M. & Seeliger, M.W. (2012). Gene therapy restores missing cone-mediated vision in the CNGA3-/- mouse model of achromatopsia. Advances in Experimental Medicine and Biology 723, 183–189.Google Scholar
Mihelec, M., Pearson, R.A., Robbie, S.J., Buch, P.K., Azam, S.A., Bainbridge, J.W., Smith, A.J., Ali, R.R. (2011). Long-term preservation of cones and improvement in visual function following gene therapy in a mouse model of Leber congenital amaurosis caused by guanylate cyclase-1 deficiency. Human Gene Therapy 22, 1179–1190.Google Scholar
Millington-Ward, S., Chadderton, N., O'Reilly, M., Palfi, A., Goldmann, T., Kilty, C., Humphries, M., Wolfrum, U., Bennett, J., Humphries, P., Kenna, P.F. & Farrar, G.J. (2011). Suppression and replacement gene therapy for autosomal dominant disease in a murine model of dominant retinitis pigmentosa. Molecular Therapy 19, 642–649.Google Scholar
Millington-Ward, S., O'Neill, B., Tuohy, G., Al-Jandal, N., Kiang, A.S., Kenna, P.F., Palfi, A., Hayden, P., Mansergh, F., Kennan, A., Humphries, P. & Farrar, G.J. (1997). Human Molecular Genetics 6, 1415–1426.Google Scholar
Min, S.H., Molday, L.L., Seeliger, M.W., Dinculescu, A., Timmers, A.M., Janssen, A., Tonagel, F., Tanimoto, N., Weber, B.H., Molday, R.S. & Hauswirth, W.W. (2005). Prolonged recovery of retinal structure/function after gene therapy in an Rs1h-deficient mouse model of x-linked juvenile retinoschisis. Molecular Therapy 12, 644–651.Google Scholar
Molday, L.L., Djajadi, H., Yan, P., Szczygiel, L., Boye, S.L., Chiodo, V.A., Gregory-Evans, K., Sarunic, M.V., Hauswirth, W.W. & Molday, R.S. (2013). RD3 gene delivery restores guanylate cyclase localization and rescues photoreceptors in the Rd3 mouse model of Leber congenital amaurosis 12. Human Molecular Genetics 22, 3894–3905.Google Scholar
Molday, R.S., Kellner, U. & Weber, B.H. (2012). X-linked juvenile retinoschisis: Clinical diagnosis, genetic analysis, and molecular mechanisms. Progress in Retinal and Eye Research 31, 195–212.Google Scholar
Mussolino, C., Sanges, D., Marrocco, E., Bonetti, C., Di Vicino, U., Marigo, V., Auricchio, A., Meroni, G. & Surace, E.M. (2011). Zinc-finger-based transcriptional repression of rhodopsin in a model of dominant retinitis pigmentosa. EMBO Molecular Medicine 3, 118–128.Google Scholar
Nakazawa, M. (2011). Effects of calcium ion, calpains, and calcium channel blockers on retinitis pigmentosa. Journal of Ophthalmology 2011, 292040.Google Scholar
Napoli, C., Lemieux, C. & Jorgensen, R. (1990). Introduction of a chimeric chalcone synthase gene into petunia results in reversible co-suppression of homologous genes in trans. Plant Cell 2, 279–289.Google Scholar
Narfström, K., Katz, M.L., Bragadottir, R., Seeliger, M., Boulanger, A., Redmond, T.M., Caro, L., Lai, C.M. & Rakoczy, P.E. (2003). Functional and structural recovery of the retina after gene therapy in the RPE65 null mutation dog. Investigative Ophthalmology & Visual Science 44, 1663–1672.Google Scholar
Narfström, K., Vaegan, , Katz, M., Bragadottir, R., Rakoczy, E.P. & Seeliger, M. (2005). Assessment of structure and function over a 3-year period after gene transfer in RPE65-/- dogs. Documenta Ophthalmologica 111, 39–48.Google Scholar
Narfström, K., Seeliger, M., Lai, C.M., Vaegan, , Katz, M., Rakoczy, E.P. & Remé, C. (2008). Morphological aspects related to long-term functional improvement of the retina in the 4 years following rAAV-mediated gene transfer in the RPE65 null mutation dog. Advances in Experimental Medicine and Biology 613, 139–146.Google Scholar
Ohnaka, M., Miki, K., Gong, Y.Y., Stevens, R., Iwase, T., Hackett, S.F. & Campochiaro, P.A. (2012). Long-term expression of glial cell line-derived neurotrophic factor slows, but does not stop retinal degeneration in a model of retinitis pigmentosa. Journal of Neurochemistry 122, 1047–1053.Google Scholar
O'Reilly, M., Palfi, A., Chadderton, N., Millington-Ward, S., Ader, M., Cronin, T., Tuohy, T., Auricchio, A., Hildinger, M., Tivnan, A., McNally, N., Humphries, M.M., Kiang, A.S., Humphries, P., Kenna, P.F. & Farrar, G.J. (2007). RNA interference-mediated suppression and replacement of human rhodopsin in vivo. American Journal of Human Genetics 81, 127–135.Google Scholar
Overlack, N., Goldmann, T., Wolfrum, U. & Nagel-Wolfrum, K. (2012). Gene repair of an Usher syndrome causing mutation by zinc-finger nuclease mediated homologous recombination. Investigative Ophthalmology & Visual Science 53, 4140–4146.Google Scholar
Palfi, A., Ader, M., Kiang, A.S., Millington-Ward, S., Clark, G., O’Reilly, M., McMahon, H.P., Kenna, P.F., Humphries, P.F. & Farrar, G.J. (2006). RNAi-based suppression and replacement of RDS-peripherin in retinal organotypic culture. Human Mutation 27, 260–268.Google Scholar
Palfi, A., Chadderton, N., McKee, A.G., Blanco-Fernandez, A., Humphries, P., Kenna, P.F., Farrar, G.J. (2012). Efficacy of co-delivery of dual AAV2/5 vectors in the murine retina and hippocampus. Human Gene Therapy 23, 847–858.Google Scholar
Palfi, A., Millington-Ward, S., Chadderton, N., O'Reilly, M., Goldmann, T., Humphries, M.M., Li, T., Wolfrum, U., Humphries, P., Kenna, P.F. & Farrar, G.J. (2010). AAV-mediated rhodopsin replacement provides therapeutic benefit in mice with a targeted disruption of the rhodopsin gene. Human Gene Therapy 21, 311–323.Google Scholar
Pang, J.-J., Dai, X., Boye, S.E., Barone, I., Boye, S.L., Mao, S., Everhart, D., Dinculescu, A., Liu, L., Umino, Y., Lei, B., Chang, B., Barlow, R., Strettoi, E. & Hauswirth, W.W. (2011). Long-term retinal function and structure rescue using capsid mutant AAV8 vector in the rd10 mouse, a model of recessive retinitis pigmentosa. Molecular Therapy 19, 234–242.Google Scholar
Pang, J.J., Deng, W.T., Dai, X., Lei, B., Everhart, D., Umino, Y., Li, J., Zhang, K., Mao, S., Boye, S.L., Liu, L., Chiodo, V.A., Liu, X., Shi, W., Tao, Y., Chang, B. & Hauswirth, W.W. (2012). AAV-mediated cone rescue in a naturally occurring mouse model of CNGA3-achromatopsia. PLoS One 7, e35250.Google Scholar
Park, T.K., Wu, Z., Kjellstrom, S., Zeng, Y., Bush, R.A., Sieving, P.A., Colosi, P. (2009). Intravitreal delivery of AAV8 retinoschisin results in cell type-specific gene expression and retinal rescue in the Rs1-KO mouse. Gene Therapy 16, 916–926.Google Scholar
Pawlyk, B.S., Bulgakov, O.V., Liu, X., Xu, X., Adamian, M., Sun, X., Khani, S.C., Berson, E.L., Sandberg, M.A. & Li, T (2010). Replacement gene therapy with a human RPGRIP1 sequence slows photoreceptor degeneration in a murine model of Leber congenital amaurosis. Human Gene Therapy 21, 993–1004.Google Scholar
Pawlyk, B.S., Smith, A.J., Buch, P.K., Adamian, M., Hong, D.H., Sandberg, M.A., Ali, R.R. & Li, T. (2005). Gene replacement therapy rescues photoreceptor degeneration in a murine model of Leber congenital amaurosis lacking RPGRIP. Investigative Ophthalmology & Visual Science 46, 3039–3045.Google Scholar
Perche, O., Doly, M. & Ranchon-Cole, I. (2007). Caspase-dependent apoptosis in light-induced retinal degeneration. Investigative Ophthalmology & Visual Science 48, 2753–2759.Google Scholar
Petrs-Silva, H., Yasumura, D., Matthes, M.T., LaVail, M.M., Lewin, A.S. & Hauswirth, W.W. (2012). Suppression of rds expression by siRNA and gene replacement strategies for gene therapy using rAAV vector. Advances in Experimental Medicine and Biology 723, 215–223.Google Scholar
Portera-Cailliau, C., Sung, C.H., Nathans, J. & Adler, R. (1994). Apoptotic photoreceptor cell death in mouse models of retinitis pigmentosa. Proceedings of the National Academy of Sciences of the United States of America 91, 974–978.Google Scholar
Ramsden, C.M., Powner, M.B., Carr, A.J., Smart, M.J., da Cruz, L. & Coffey, P.J. (2013). Stem cells in retinal regeneration: Past, present and future. Development 140, 2576–2585.Google Scholar
Reich, S.J., Auricchio, A., Hildinger, M., Glover, E., Maguire, A.M., Wilson, J.M. & Bennett, J. (2003). Efficient trans-splicing in the retina expands the utility of adeno-associated virus as a vector for gene therapy. Human Gene Therapy 14, 37–44.Google Scholar
Sahel, J.A. & Roska, B. (2013). Gene therapy for blindness. Annual Review of Neuroscience 36, 467–488.Google Scholar
Sano, Y., Furuta, A., Setsuie, R., Kikuchi, H., Wang, Y.L., Sakurai, M., Kwon, J., Noda, M. & Wada, K. (2006). Photoreceptor cell apoptosis in the retinal degeneration of Uchl3-deficient mice. American Journal of Pathology 169, 132–141.Google Scholar
Schlichtenbrede, F.C., da Cruz, L., Stephens, C., Smith, A.J., Georgiadis, A., Thrasher, A.J., Bainbridge, J.W., Seeliger, M.W. & Ali, R.R. (2003). Long-term evaluation of retinal function in Prph2Rd2/Rd2 mice following AAV-mediated gene replacement therapy. The Journal of Gene Medicine 5, 757–764.Google Scholar
Schön, C., Biel, M. & Michalakis, S. (2013). Gene replacement therapy for retinal CNG channelopathies. Molecular Genetics and Genomics 288, 459–467.Google Scholar
Shan, H., Ji, D., Barnard, A.R., Lipinski, D.M., You, Q., Lee, E.J., Kamalden, T.A., Sun, X. & MacLaren, R.E. (2011). AAV-mediated gene transfer of human X-linked inhibitor of apoptosis protects against oxidative cell death in human RPE cells. Investigative Ophthalmology & Visual Science 52, 9591–9597.Google Scholar
Shanks, M.E., Downes, S.M., Copley, R.R., Lise, S., Broxholme, J., Hudspith, K.A., Kwasniewska, A., Davies, W.I., Hankins, M.W., Packham, E.R., Clouston, P., Seller, A., Wilkie, A.O., Taylor, J.C., Ragoussis, J., Németh, A.H. (2012). Next-generation sequencing (NGS) as a diagnostic tool for retinal degeneration reveals a much higher detection rate in early-onset disease. European Journal of Human Genetics 21, 1031.Google Scholar
Shepherd, R.K., Shivdasani, M.N., Nayagam, D.A., Williams, C.E. & Blamey, P.J. (2013). Visual prostheses for the blind. Trends Biotechnology 31, 562–571.Google Scholar
Simonelli, F., Maguire, A.M., Testa, F., Pierce, E.A., Mingozzi, F., Bennicelli, J.L., Rossi, S., Marshall, K., Banfi, S., Surace, E.M., Sun, J., Redmond, T.M., Zhu, X., Shindler, K.S., Ying, G.S., Ziviello, C., Acerra, C., Wright, J.F., McDonnell, J.W., High, K.A., Bennett, J. & Auricchio, A. (2010). Gene therapy for Leber's congenital amaurosis is safe and effective through 1.5 years after vector administration. Molecular Therapy 18, 643–650.Google Scholar
Simons, D.L., Boye, S.L., Hauswirth, W.W. & Wu, S.M. (2011). Gene therapy prevents photoreceptor death and preserves retinal function in a Bardet-Biedl syndrome mouse model. Proceedings of the National Academy of Sciences of the United States of America 108, 6276–6281.Google Scholar
Sivak, J.M. (2013). The aging eye: Common degenerative mechanisms between the Alzheimer's brain and retinal disease. Investigative Ophthalmology & Visual Science 54, 871–880.Google Scholar
Smith, A.J., Bainbridge, J.W., Ali, R.R. (2012). Gene supplementation therapy for recessive forms of inherited retinal dystrophies. Gene Therapy 19, 154–161.Google Scholar
Smith, A.J., Schlichtenbrede, F.C., Tschernutter, M., Bainbridge, J.W., Thrasher, A.J. & Ali, R.R. (2003). AAV-mediated gene transfer slows photoreceptor loss in the RCS rat model of retinitis pigmentosa. Molecular Therapy 8, 188–195.Google Scholar
Souied, E.H., Reid, S.N., Piri, N.I., Lerner, L.E., Nusinowitz, S. & Farber, D.B. (2008). Non-invasive gene transfer by iontophoresis for therapy of an inherited retinal degeneration. Experimental Eye Research 87, 168–175.Google Scholar
Sun, X., Pawlyk, B., Xu, X., Liu, X., Bulgakov, O.V., Adamian, M., Sandberg, M.A., Khani, S.C., Tan, M.H., Smith, A.J., Ali, R.R. & Li, T. (2010). Gene therapy with a promoter targeting both rods and cones rescues retinal degeneration caused by AIPL1 mutations. Gene Therapy 17, 117–131.Google Scholar
Surace, E.M., Domenici, L., Cortese, K., Cotugno, G., Di Vicino, U., Venturi, C., Cellerino, A., Marigo, V., Tacchetti, C., Ballabio, A. & Auricchio, A. (2005). Amelioration of both functional and morphological abnormalities in the retina of a mouse model of ocular albinism following AAV-mediated gene transfer. Molecular Therapy 12, 652–658.Google Scholar
Takada, Y., Vijayasarathy, C., Zeng, Y., Kjellstrom, S., Bush, R.A. & Sieving, P.A. (2008). Synaptic pathology in retinoschisis knockout (Rs1-/y) mouse retina and modification by rAAV-Rs1 gene delivery. Investigative Ophthalmology & Visual Science 49, 3677–3686.Google Scholar
Tam, L.C., Kiang, A.S., Campbell, M., Keaney, J., Farrar, G.J., Humphries, M.M., Kenna, P.F. & Humphries, P. (2010). Prevention of autosomal dominant retinitis pigmentosa by systemic drug therapy targeting heat shock protein 90 (Hsp90). Human Molecular Genetics 19, 4421–4436.Google Scholar
Tam, L.C., Kiang, A.S., Kennan, A., Kenna, P.F., Chadderton, N., Ader, M., Palfi, A., Aherne, A., Ayuso, C., Campbell, M., Reynolds, A., McKee, A., Humphries, M.M., Farrar, G.J. & Humphries, P. (2008). Therapeutic benefit derived from RNAi-mediated ablation of IMPDH1 transcripts in a murine model of autosomal dominant retinitis pigmentosa (RP10). Human Molecular Genetics 17, 2084–2100.Google Scholar
Tan, M.H., Smith, A.J., Pawlyk, B., Xu, X., Liu, X., Bainbridge, J.B., Basche, M., McIntosh, J., Tran, H.V., Nathwani, A., Li, T. & Ali, R.R. (2009). Gene therapy for retinitis pigmentosa and Leber congenital amaurosis caused by defects in AIPL1: Effective rescue of mouse models of partial and complete Aipl1 deficiency using AAV2/2 and AAV2/8 vectors. Human Molecular Genetics 18, 2099–2114. Erratum in: Hum Mol Genet., 2010, 19(4): 735.Google Scholar
Testa, F., Surace, E.M., Rossi, S., Marrocco, E., Gargiulo, A., Di Iorio, V., Ziviello, C., Nesti, A., Fecarotta, S., Bacci, M.L., Giunti, M., Della Corte, M., Banfi, S., Auricchio, A. & Simonelli, F. (2011). Evaluation of Italian patients with Leber congenital amaurosis due to AIPL1 mutations highlights the potential applicability of gene therapy. Investigative Ophthalmology & Visual Science 52, 5618–5624.Google Scholar
Thyagarajan, S., van Wyk, M., Lehmann, K., Löwel, S., Feng, G. & Wässle, H. (2010). Visual function in mice with photoreceptor degeneration and transgenic expression of channelrhodopsin 2 in ganglion cells. The Journal of Neuroscience 30, 8745–8758.Google Scholar
Tolmachova, T., Tolmachov, O.E., Barnard, A.R., de Silva, S.R., Lipinski, D.M., Walker, N.J., Maclaren, R.E. & Seabra, M.C. (2013). Functional expression of Rab escort protein 1 following AAV2-mediated gene delivery in the retina of choroideremia mice and human cells ex vivo. Journal of Molecular Medicine (Berl) 91, 825–837.Google Scholar
Tolmachova, T., Tolmachov, O.E., Wavre-Shapton, S.T., Tracey-White, D., Futter, C.E. & Seabra, M.C. (2012). CHM/REP1 cDNA delivery by lentiviral vectors provides functional expression of the transgene in the retinal pigment epithelium of choroideremia mice. The Journal of Gene Medicine 14, 158–168.Google Scholar
Tomita, H., Sugano, E., Fukazawa, Y., Isago, H., Sugiyama, Y., Hiroi, T., Ishizuka, T., Mushiake, H., Kato, M., Hirabayashi, M., Shigemoto, R., Yawo, H. & Tamai, M. (2009). Visual properties of transgenic rats harboring the channelrhodopsin-2 gene regulated by the thy-1.2 promoter. PLoS One 4, e7679.Google Scholar
Tomita, H., Sugano, E., Isago, H., Hiroi, T., Wang, Z., Ohta, E. & Tamai, M. (2010). Channelrhodopsin-2 gene transduced into retinal ganglion cells restores functional vision in genetically blind rats. Experimental Eye Research 90, 429–436.Google Scholar
Tosi, J., Sancho-Pelluz, J., Davis, R.J., Hsu, C.W., Wolpert, K.V., Sengillo, J.D., Lin, C.S. & Tsang, S.H. (2011). Lentivirus-mediated expression of cDNA and shRNA slows degeneration in retinitis pigmentosa. Experimental Biology and Medicine (Maywood) 236, 1211–1217.Google Scholar
Touchard, E., Heiduschka, P., Berdugo, M., Kowalczuk, L., Bigey, P., Chahory, S, Gandolphe, C., Jeanny, J.C. & Behar-Cohen, F. (2012). Non-viral gene therapy for GDNF production in RCS rat: The crucial role of the plasmid dose. Gene Therapy 19, 886–898.Google Scholar
Trapani, I., Colella, P., Sommella, A., Iodice, C., Cesi, G., De Simone, S., Marrocco, E., Rossi, S., Giunti, M., Palfi, A., Jane Farrar, G., Polishchuk, R. & Auricchio, A. (2013). Effective delivery of large genes to the retina by dual AAV vectors. EMBO Molecular Medicine doi: 10.1002/emmm.201302948.Google Scholar
Trifunović, D., Sahaboglu, A., Kaur, J., Mencl, S., Zrenner, E., Ueffing, M., Arango-Gonzalez, B. & Paquet-Durand, F. (2012). Neuroprotective strategies for the treatment of inherited photoreceptor degeneration. Current Molecular Medicine 12, 598–612.Google Scholar
Tschernutter, M., Schlichtenbrede, F.C., Howe, S., Balaggan, K.S., Munro, P.M., Bainbridge, J.W., Thrasher, A.J., Smith, A.J. & Ali, R.R. (2005). Long-term preservation of retinal function in the RCS rat model of retinitis pigmentosa following lentivirus-mediated genetherapy. Gene Therapy 12, 694–701.Google Scholar
Usui, S., Komeima, K., Lee, S.Y., Jo, Y.J., Ueno, S., Rogers, B.S., Wu, Z., Shen, J., Lu, L., Oveson, B.C., Rabinovitch, P.S. & Campochiaro, P.A. (2009). Increased expression of catalase and superoxide dismutase 2 reduces cone cell death in retinitis pigmentosa. Molecular Therapy 17, 778–786.Google Scholar
Usui, S., Oveson, B.C., Iwase, T., Lu, L., Lee, S.Y., Jo, Y.J., Wu, Z., Choi, E.Y., Samulski, R.J. & Campochiaro, P.A. (2011). Overexpression of SOD in retina: Need for increase in H2O2-detoxifying enzyme in same cellular compartment. Free Radical Biology & Medicine 51, 1347–1354.Google Scholar
Vandenberghe, L.H. & Auricchio, A. (2012). Novel adeno-associated viral vectors for retinal gene therapy. Gene Therapy 19, 162–168.Google Scholar
Vasireddy, V., Mills, J.A., Gaddameedi, R., Basner-Tschakarjan, E., Kohnke, M., Black, A.D., Alexandrov, K., Zhou, S., Maguire, A.M., Chung, D.C., Mac, H., Sullivan, L., Gadue, P., Bennicelli, J.L., French, D.L. & Bennett, J. (2013). AAV-mediated gene therapy for choroideremia: Preclinical studies in personalized models. PLoS One 8, e61396.Google Scholar
Verrier, J.D., Madorsky, I., Coggin, W.E., Geesey, M., Hochman, M., Walling, E., Daroszewski, D., Eccles, K.S., Ludlow, R. & Semple-Rowland, S.L. (2011). Bicistronic lentiviruses containing a viral 2A cleavage sequence reliably co-express two proteins and restore vision to an animal model of LCA1. PLoS One 6, e20553.Google Scholar
Volgraf, M., Gorostiza, P., Numano, R., Kramer, R.H., Isacoff, E.Y. & Trauner, D. (2006). Allosteric control of an ionotropic glutamate receptor with an optical switch. Nature Chemical Biology 2, 47–52.Google Scholar
Vollrath, D., Feng, W., Duncan, J.L., Yasumura, D., D'Cruz, P.M., Chappelow, A., Matthes, M.T., Kay, M.A. & LaVail, M.M. (2001). Correction of the retinal dystrophy phenotype of the RCS rat by viral gene transfer of Mertk. Proceedings of the National Academy of Sciences of the United States of America 98, 12584–12589.Google Scholar
Wert, K.J., Davis, R.J., Sancho-Pelluz, J., Nishina, P.M. & Tsang, S.H. (2013). Gene therapy provides long-term visual function in a pre-clinical model of retinitis pigmentosa. Human Molecular Genetics 22, 558–567.Google Scholar
Wert, K.J., Sancho-Pelluz, J. & Tsang, S.H. (2014). Mid-stage intervention achieves similar efficacy as conventional early-stage treatment using gene therapy in a pre-clinical model of retinitis pigmentosa. Human Molecular Genetics 23, 514–523.Google Scholar
Willett, K. & Bennett, J. (2013). Immunology of AAV-mediated gene transfer in the eye. Frontiers in Immunology 4, 261.Google Scholar
Wu, Z., Yang, H. & Colosi, P. (2010). Effect of genome size on AAV vector packaging. Molecular Therapy 18, 80–86.Google Scholar
Yang, Y., Mohand-Said, S., Danan, A., Simonutti, M., Fontaine, V., Clérin, E., Picaud, S., Léveillard, T. & Sahel, J.A. (2009). Functional cone rescue by RdCVF protein in a dominant model of retinitis pigmentosa. Molecular Therapy 17, 787–795.Google Scholar
Yao, J., Jia, L., Khan, N., Zheng, Q.D., Moncrief, A., Hauswirth, W.W., Thompson, D.A. & Zacks, (2012). Caspase inhibition with XIAP as an adjunct to AAV vector gene-replacement therapy: Improving efficacy and prolonging the treatment window. PLoS One 7, e37197.Google Scholar
Yeh, C.Y., Goldstein, O., Kukekova, A.V., Holley, D., Knollinger, A.M., Huson, H.J., Pearce-Kelling, S.E., Acland, G.M. & Komáromy, A.M. (2013). Genomic deletion of CNGB3 is identical by descent in multiple canine breeds and causes achromatopsia. BMC Genetics 14, 27.Google Scholar
Yu, H., Mehta, A., Wang, G., Hauswirth, W.W., Chiodo, V., Boye, S.L. & Guy, J. (2013). Next-generation sequencing of mitochondrial targeted AAV transfer of human ND4 in mice. Molecular Vision 19, 1482–1491.Google Scholar
Yu, H., Ozdemir, S.S., Koilkonda, R.D., Chou, T.H., Porciatti, V., Chiodo, V., Boye, S.L., Hauswirth, W.W., Lewin, A.S. & Guy, J. (2012). Mutant NADH dehydrogenase subunit 4 gene delivery to mitochondria by targeting sequence-modified adeno-associated virus induces visual loss and optic atrophy in mice. Molecular Vision 18, 1668–1683.Google Scholar
Yu-Wai-Man, P., Griffiths, P.G. & Chinnery, P.F. (2011). Mitochondrial optic neuropathies – Disease mechanisms and therapeutic strategies. Progress in Retinal Eye Research 30, 81–114.Google Scholar
Yu-Wai-Man, P., Griffiths, P.G., Hudson, G. & Chinnery, P.F. (2009). Inherited mitochondrial optic neuropathies. Journal of Medical Genetics 46, 145–158.Google Scholar
Zeng, Y., Takada, Y., Kjellstrom, S., Hiriyanna, K., Tanikawa, A., Wawrousek, E., Smaoui, N., Caruso, R., Bush, R.A. & Sieving, P.A. (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. Investigative Ophthalmology & Visual Science 45, 3279–3285.Google Scholar
Zhang, F., Gradinaru, V., Adamantidis, A.R., Durand, R., Airan, R.D., de Lecea, L. & Deisseroth, K. (2010). Optogenetic interrogation of neural circuits: Technology for probing mammalian brain structures. Nature Protocols 5, 439–456.Google Scholar
Zhang, Y., Ivanova, E., Bi, A. & Pan, Z.H. (2009). Ectopic expression of multiple microbial rhodopsins restores ON and OFF light responses in retinas with photoreceptor degeneration. The Journal of Neuroscience 29, 9186–9196.Google Scholar
Zolotukhin, S., Potter, M., Zolotukhin, I., Sakai, Y., Loiler, S., Fraites, T.J. Jr., Chiodo, V.A., Phillipsberg, T., Muzyczka, N., Hauswirth, W.W., Flotte, T.R., Byrne, B.J. & Snyder, R.O. (2002). Production and purification of serotype 1, 2, and 5 recombinant adeno-associated viral vectors. Methods 28, 158–167.Google Scholar
Zou, J., Luo, L., Shen, Z., Chiodo, V.A., Ambati, B.K., Hauswirth, W.W. & Yang, J. (2011). Whirlin replacement restores the formation of the USH2 protein complex in whirlin knockout photoreceptors. Investigative Ophthalmology & Visual Science 52, 2343–2351.Google Scholar