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
Abstract
Leber congenital amaurosis (LCA) is a group of autosomal recessive blinding retinal diseases that are incurable. One molecular form is caused by mutations in the RPE65 (retinal pigment epithelium-specific 65-kDa) gene. A recombinant adeno-associated virus serotype 2 (rAAV2) vector, altered to carry the human RPE65 gene (rAAV2-CBSB-hRPE65), restored vision in animal models with RPE65 deficiency. A clinical trial was designed to assess the safety of rAAV2-CBSB-hRPE65 in subjects with RPE65-LCA. Three young adults (ages 21–24 years) with RPE65-LCA received a uniocular subretinal injection of 5.96 × 1010 vector genomes in 150 μl and were studied with follow-up examinations for 90 days. Ocular safety, the primary outcome, was assessed by clinical eye examination. Visual function was measured by visual acuity and dark-adapted full-field sensitivity testing (FST); central retinal structure was monitored by optical coherence tomography (OCT). Neither vector-related serious adverse events nor systemic toxicities were detected. Visual acuity was not significantly different from baseline; one patient showed retinal thinning at the fovea by OCT. All patients self-reported increased visual sensitivity in the study eye compared with their control eye, especially noticeable under reduced ambient light conditions. The dark-adapted FST results were compared between baseline and 30–90 days after treatment. For study eyes, sensitivity increases from mean baseline were highly significant (p < 0.001); whereas, for control eyes, sensitivity changes were not significant (p = 0.99). Comparisons are drawn between the present work and two other studies of ocular gene therapy for RPE65-LCA that were carried out contemporaneously and reported.
Get full access to this article
View all available purchase options and get full access to this article.
References
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 blindnessNat. Genet.2892-95. 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., and Bennett, J. (2001). Gene therapy restores vision in a canine model of childhood blindness. Nat. Genet. 28, 92–95.
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 blindnessMol. Ther.121072-1082. 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., and 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. Mol. Ther. 12, 1072–1082.
Aguirre G.K.Komaromy A.M.Cideciyan A.V.Brainard D.H.Aleman T.S.Roman A.J.Avants B.B.Gee J.C.Korczykowski M.Hauswirth W.W.Acland G.M.Aguirre G.D.Jacobson S.G.2007. Canine and human visual cortex intact and responsive despite early retinal blindness from RPE65 mutationPLoS Med.4e230. Aguirre, G.K., Komaromy, A.M., Cideciyan, A.V., Brainard, D.H., Aleman, T.S., Roman, A.J., Avants, B.B., Gee, J.C., Korczykowski, M., Hauswirth, W.W., Acland, G.M., Aguirre, G.D., and Jacobson, S.G. (2007). Canine and human visual cortex intact and responsive despite early retinal blindness from RPE65 mutation. PLoS Med. 4, e230.
Aleman T.S.Cideciyan A.V.Sumaroka A.Windsor E.A.Herrera W.White D.A.Kaushal S.Naidu A.Roman A.J.Schwartz S.B.Stone E.M.Jacobson S.G.2008. Retinal laminar architecture in human retinitis pigmentosa caused by rhodopsin gene mutationsInvest. Ophthalmol. Vis. Sci.491580-1590. Aleman, T.S., Cideciyan, A.V., Sumaroka, A., Windsor, E.A., Herrera, W., White, D.A., Kaushal, S., Naidu, A., Roman, A.J., Schwartz, S.B., Stone, E.M., and Jacobson, S.G. (2008). Retinal laminar architecture in human retinitis pigmentosa caused by rhodopsin gene mutations. Invest. Ophthalmol. Vis. Sci. 49, 1580–1590.
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 amaurosisN. Engl. J. Med.3582231-2239. 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., and Ali, R.R. (2008). Effect of gene therapy on visual function in Leber's congenital amaurosis. N. Engl. J. Med. 358, 2231–2239.
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.AMaguire A.M.Bennett J.2008. Reversal of blindness in animal models of Leber congenital amaurosis using optimized AAV2-mediated gene transferMol. Ther.16458-465. 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., and Bennett, J. (2008). Reversal of blindness in animal models of Leber congenital amaurosis using optimized AAV2-mediated gene transfer. Mol. Ther. 16, 458–465.
Bok D.2004. Gene therapy of retinal dystrophies: Achievements, challenges and prospectsNovartis Found. Symp.2554-16177-178. Bok, D. (2004). Gene therapy of retinal dystrophies: Achievements, challenges and prospects. Novartis Found. Symp. 255, 4–16, 177–178.
Booij J.C.Florijn R.J.ten Brink J.B.Loves W.Meire F.van Schooneveld M.J.de Jong P.T.Bergen A.A.2005. Identification of mutations in the AIPL1, CRB1, GUCY2D, RPE65, and RPGRIP1 genes in patients with juvenile retinitis pigmentosaJ. Med. Genet.42e67. Booij, J.C., Florijn, R.J., ten Brink, J.B., Loves, W., Meire, F., van Schooneveld, M.J., de Jong, P.T., and Bergen, A.A. (2005). Identification of mutations in the AIPL1, CRB1, GUCY2D, RPE65, and RPGRIP1 genes in patients with juvenile retinitis pigmentosa. J. Med. Genet. 42, e67.
Brantly M.L.Spencer L.T.Humphries M.Conlon T.J.Spencer C.T.Poireir A.Garlington W.Baker D.Song S.Berns K.I.Muzuczka N.Snyder R.O.Byrne B.J.Flotte T.R.2006. Phase I trial of intramuscular injection of a recombinant adeno-associated virus serotype 2 α1-antitrypsin (AAT) vector in AAT-deficient adultsHum. Gene Ther.171177-1186. Brantly, M.L., Spencer, L.T., Humphries, M., Conlon, T.J., Spencer, C.T., Poireir, A., Garlington, W., Baker, D., Song, S., Berns, K.I., Muzuczka, N., Snyder, R.O., Byrne, B.J., and Flotte, T.R. (2006). Phase I trial of intramuscular injection of a recombinant adeno-associated virus serotype 2 α1-antitrypsin (AAT) vector in AAT-deficient adults. Hum. Gene Ther. 17, 1177–1186.
Burton T.C.1982. Recovery of visual acuity after retinal detachment involving the maculaTrans. Am. Ophthalmol. Soc.80475-497. Burton, T.C. (1982). Recovery of visual acuity after retinal detachment involving the macula. Trans. Am. Ophthalmol. Soc. 80, 475–497.
Dejneka N.S.Surace E.M.Aleman T.S.Cideciyan A.V.Lyubarsky A.Savchenko A.Redmond T.M.Tang W.Wei Z.Rex T.S.Glover E.Maguire A.M.Pugh E.N.Jacobson S.G.Bennett J.2004. In utero gene therapy rescues vision in a murine model of congenital blindnessMol. Ther.9182-188. Dejneka, N.S., Surace, E.M., Aleman, T.S., Cideciyan, A.V., Lyubarsky, A., Savchenko, A., Redmond, T.M., Tang, W., Wei, Z., Rex, T.S., Glover, E., Maguire, A.M., Pugh, E.N., Jacobson, S.G., and Bennett, J. (2004). In utero gene therapy rescues vision in a murine model of congenital blindness. Mol. Ther. 9, 182–188.
Donsante A.Vogler C.Muzyczka N.Crawford J.M.Barker J.Flotte T.Campbell-Thompson M.Daly T.Sands M.S.2001. Observed incidence of tumorigenesis in long-term rodent studies of rAAV vectorsGene Ther.81343-1346. Donsante, A., Vogler, C., Muzyczka, N., Crawford, J.M., Barker, J., Flotte, T., Campbell-Thompson, M., Daly, T., and Sands, M.S. (2001). Observed incidence of tumorigenesis in long-term rodent studies of rAAV vectors. Gene Ther. 8, 1343–1346.
Felius J.Thompson D.A.Khan N.W.Bingham E.L.Jamison J.A.Kemp J.A.Sieving P.A.2002. Clinical course and visual function in a family with mutations in the RPE65 geneArch. Ophthalmol.12055-61. Felius, J., Thompson, D.A., Khan, N.W., Bingham, E.L., Jamison, J.A., Kemp, J.A., and Sieving, P.A. (2002). Clinical course and visual function in a family with mutations in the RPE65 gene. Arch. Ophthalmol. 120, 55–61.
Ferris F.L. IIIKassoff A.Bresnick G.H.Bailey I.1982. New visual acuity charts for clinical researchAm. J. Ophthalmol.9491-96. Ferris, F.L., III, Kassoff, A., Bresnick, G.H., and Bailey, I. (1982). New visual acuity charts for clinical research. Am. J. Ophthalmol. 94, 91–96.
Fu T.M.Dubey S.A.Mehrotra D.V.Freed D.C.Trigona W.L.Adams-Muhler L.Clair J.H.Evans T.G.Steigbigel R.Jacobson J.M.Goepfert P.A.Mulligan M.J.Kalams S.A.Rinaldo C.Zhu L.Cox K.S.Guan L.Long R.Persaud N.Caulfield M.J.Sadoff J.C.Emini E.A.Thaler S.Shiver J.W.2007. Evaluation of cellular immune responses in subjects chronically infected with HIV type 1AIDS Res. Hum. Retroviruses2367-76. Fu, T.M., Dubey, S.A., Mehrotra, D.V., Freed, D.C., Trigona, W.L., Adams-Muhler, L., Clair, J.H., Evans, T.G., Steigbigel, R., Jacobson, J.M., Goepfert, P.A., Mulligan, M.J., Kalams, S.A., Rinaldo, C., Zhu, L., Cox, K.S., Guan, L., Long, R., Persaud, N., Caulfield, M.J., Sadoff, J.C., Emini, E.A., Thaler, S., and Shiver, J.W. (2007). Evaluation of cellular immune responses in subjects chronically infected with HIV type 1. AIDS Res. Hum. Retroviruses 23, 67–76.
Grimm D.Kern A.Rittner K.Kleinschmidt J.A.1998. Novel tools for production and purification of recombinant adenoassociated virus vectorsHum. Gene Ther.92745-2760. Grimm, D., Kern, A., Rittner, K., and Kleinschmidt, J.A. (1998). Novel tools for production and purification of recombinant adenoassociated virus vectors. Hum. Gene Ther. 9, 2745–2760.
Hernandez Y.J.Wang J.Kearns W.G.Loiler S.Poirier A.Flotte T.R.1999. Latent adeno-associated virus infection elicits humoral but not cell-mediated immune responses in a nonhuman primate modelJ. Virol.738549-8558. Hernandez, Y.J., Wang, J., Kearns, W.G., Loiler, S., Poirier, A., and Flotte, T.R. (1999). Latent adeno-associated virus infection elicits humoral but not cell-mediated immune responses in a nonhuman primate model. J. Virol. 73, 8549–8558.
Hogan M.J.Kimura S.J.Thygeson P.1959. Signs and symptoms of uveitis. I. Anterior uveitisAm. J. Ophthalmol.47155-170. Hogan, M.J., Kimura, S.J., and Thygeson, P. (1959). Signs and symptoms of uveitis. I. Anterior uveitis. Am. J. Ophthalmol. 47, 155–170.
Hogan M.J.Alvardo J.A.Weddell J.E.1971. RetinaHistology of the Human EyeW.B. SaundersPhiladelphia, PA491. Hogan, M.J., Alvardo, J.A., and Weddell, J.E. (1971). Retina. In Histology of the Human Eye. (W.B. Saunders, Philadelphia, PA) p. 491.
Huang Y.Cideciyan A.V.Papastergiou G.I.Banin E.Semple-Rowland S.L.Milam A.H.Jacobson S.G.1998. Relation of optical coherence tomography to microanatomy in normal and rd chickensInvest. Ophthalmol. Vis. Sci.392405-2416. Huang, Y., Cideciyan, A.V., Papastergiou, G.I., Banin, E., Semple-Rowland, S.L., Milam, A.H., and Jacobson, S.G. (1998). Relation of optical coherence tomography to microanatomy in normal and rd chickens. Invest. Ophthalmol. Vis. Sci. 39, 2405–2416.
Jacobson S.G.Aleman T.S.Cideciyan A.V.Sumaroka A.Schwartz S.B.Windsor E.A.Traboulsi E.I.Heon E.Pittler J.Milam A.H.Maguire A.M.Palczewski K.Stone E.M.Bennett J.2005. Identifying photoreceptors in blind eyes caused by RPE65 mutations: Prerequisite for human gene therapy successProc. Natl. Acad. Sci. U.S.A.1026177-6182. Jacobson, S.G., Aleman, T.S., Cideciyan, A.V., Sumaroka, A., Schwartz, S.B., Windsor, E.A., Traboulsi, E.I., Heon, E., Pittler, J., Milam, A.H., Maguire, A.M., Palczewski, K., Stone, E.M., and Bennett, J. (2005). Identifying photoreceptors in blind eyes caused by RPE65 mutations: Prerequisite for human gene therapy success. Proc. Natl. Acad. Sci. U.S.A. 102, 6177–6182.
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.2006a. Safety of recombinant adeno-associated virus type 2-RPE65 vector delivered by ocular subretinal injectionMol. Ther.131074-1084. 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., and Hauswirth, W.W. (2006a). Safety of recombinant adeno-associated virus type 2-RPE65 vector delivered by ocular subretinal injection. Mol. Ther. 13, 1074–1084.
Jacobson S.G.Boye S.L.Aleman T.S.Conlon T.J.Zeiss C.J.Roman A.J.Cideciyan A.V.Schwartz S.B.Komaromy A.M.Doobrajh M.Cheung A.Y.Sumaroka A.Pearce-Kelling S.E.Aguirre G.D.Kaushal S.Maguire A.M.Flotte T.R.Hauswirth W.W.2006b. Safety in nonhuman primates of ocular AAV2-RPE65, a candidate treatment for blindness in Leber congenital amaurosisHum. Gene Ther.17845-858. Jacobson, S.G., Boye, S.L., Aleman, T.S., Conlon, T.J., Zeiss, C.J., Roman, A.J., Cideciyan, A.V., Schwartz, S.B., Komaromy, A.M., Doobrajh, M., Cheung, A.Y., Sumaroka, A., Pearce-Kelling, S.E., Aguirre, G.D., Kaushal, S., Maguire, A.M., Flotte, T.R., and Hauswirth, W.W. (2006b). Safety in nonhuman primates of ocular AAV2-RPE65, a candidate treatment for blindness in Leber congenital amaurosis. Hum. Gene Ther. 17, 845–858.
Jacobson S.G.Cideciyan A.V.Sumaroka A.Aleman T.S.Schwartz S.B.Windsor E.A.Roman A.J.Stone E.M.Macdonald I.M.2006c. Remodeling of the human retina in choroideremia: Rab escort protein 1 (REP-1) mutationsInvest. Ophthalmol. Vis. Sci.474113-4120. Jacobson, S.G., Cideciyan, A.V., Sumaroka, A., Aleman, T.S., Schwartz, S.B., Windsor, E.A., Roman, A.J., Stone, E.M., and Macdonald, I.M. (2006c). Remodeling of the human retina in choroideremia: Rab escort protein 1 (REP-1) mutations. Invest. Ophthalmol. Vis. Sci. 47, 4113–4120.
Jacobson S.G.Aleman T.S.Cideciyan A.V.Heon E.Golczak M.Beltran W.A.Sumaroka A.Schwartz S.B.Roman A.J.Windsor E.A.Wilson J.M.Aguirre G.D.Stone E.M.Palczewski K.2007. Human cone photoreceptor dependence on RPE65 isomeraseProc. Natl. Acad. Sci. U.S.A.10415123-15128. Jacobson, S.G., Aleman, T.S., Cideciyan, A.V., Heon, E., Golczak, M., Beltran, W.A., Sumaroka, A., Schwartz, S.B., Roman, A.J., Windsor, E.A., Wilson, J.M., Aguirre, G.D., Stone, E.M., and Palczewski, K. (2007). Human cone photoreceptor dependence on RPE65 isomerase. Proc. Natl. Acad. Sci. U.S.A. 104, 15123–15128.
Jacobson S.G.Cideciyan A.V.Aleman T.S.Sumaroka Windsor E.A.Schwartz S.B.Heon EStone E.M2008. Photoreceptor layer topography in children with Leber congenital amaurosis caused by RPE65 mutationsInvest. Ophthalmol. Vis. Sci.June6[Epub ahead of print] Jacobson, S.G., Cideciyan, A.V., Aleman, T.S., Sumaroka, Windsor, E.A., Schwartz, S.B., Heon, E. and Stone, E.M. (2008). Photoreceptor layer topography in children with Leber congenital amaurosis caused by RPE65 mutations. Invest. Ophthalmol. Vis. Sci. June 6 [Epub ahead of print].
Ladas J.G.Wheeler N.C.Morhun P.J.Rimmer S.O.Holland G.N.2005. Laser flare-cell photometry: Methodology and clinical applicationsSurv. Ophthalmol.5027-47. Ladas, J.G., Wheeler, N.C., Morhun, P.J., Rimmer, S.O., and Holland, G.N. (2005). Laser flare-cell photometry: Methodology and clinical applications. Surv. Ophthalmol. 50, 27–47.
Lorenz B.Gyurus P.Preising M.Bremser D.Gu S.Andrassi M.Gerth C.Gal A.2000. Early-onset severe rod–cone dystrophy in young children with RPE65 mutationsInvest. Ophthalmol. Vis. Sci.412735-2742. Lorenz, B., Gyurus, P., Preising, M., Bremser, D., Gu, S., Andrassi, M., Gerth, C., and Gal, A. (2000). Early-onset severe rod–cone dystrophy in young children with RPE65 mutations. Invest. Ophthalmol. Vis. Sci. 41, 2735–2742.
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. Safety and efficacy of gene transfer for Leber's congenital amaurosisN. Engl. J. Med.3582240-2248. 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., and Bennett, J. (2008). Safety and efficacy of gene transfer for Leber's congenital amaurosis. N. Engl. J. Med. 358, 2240–2248.
Milam A.H.Li Z.Y.Fariss R.N.1998. Histopathology of the human retina in retinitis pigmentosaProg. Retin. Eye Res.17175-205. Milam, A.H., Li, Z.Y., and Fariss, R.N. (1998). Histopathology of the human retina in retinitis pigmentosa. Prog. Retin. Eye Res. 17, 175–205.
Miller J.W.2008. Preliminary results of gene therapy for retinal degenerationN. Engl. J. Med.3582282-2284. Miller, J.W. (2008). Preliminary results of gene therapy for retinal degeneration. N. Engl. J. Med. 358, 2282–2284.
Morimura H.Fishman G.A.Grover S.A.Fulton A.B.Berson E.L.Dryja T.P.1998. Mutations in the RPE65 gene in patients with autosomal recessive retinitis pigmentosa or Leber congenital amaurosisProc. Natl. Acad. Sci. U.S.A.953088-3093. Morimura, H., Fishman, G.A., Grover, S.A., Fulton, A.B., Berson, E.L., and Dryja, T.P. (1998). Mutations in the RPE65 gene in patients with autosomal recessive retinitis pigmentosa or Leber congenital amaurosis. Proc. Natl. Acad. Sci. U.S.A. 95, 3088–3093.
Moshfeghi A.A.Salam G.A.Deramo V.A.Shakin E.P.Ferrone P.J.Shakin J.L.Fastenberg D.M.2003. Management of macular holes that develop after retinal detachment repairAm. J. Ophthalmol.136895-899. Moshfeghi, A.A., Salam, G.A., Deramo, V.A., Shakin, E.P., Ferrone, P.J., Shakin, J.L., and Fastenberg, D.M. (2003). Management of macular holes that develop after retinal detachment repair. Am. J. Ophthalmol. 136, 895–899.
Nussenblatt R.B.Palestine A.G.Chan C.C.Roberge F.1985. Standardization of vitreal inflammatory activity in intermediate and posterior uveitisOphthalmology92467-471. Nussenblatt, R.B., Palestine, A.G., Chan, C.C., and Roberge, F. (1985). Standardization of vitreal inflammatory activity in intermediate and posterior uveitis. Ophthalmology 92, 467–471.
Pang J.J.Chang B.Hawes N.L.Hurd R.E.Davisson M.T.Li J.Noorwez S.M.Malhotra R.McDowell J.H.Kaushal S.Hauswirth W.W.Nusinowitz S.Thompson D.A.Heckenlively J.R.2005. Retinal degeneration 12 (rd12): A new, spontaneously arising mouse model for human Leber congenital amaurosis (LCA)Mol. Vis.11152-162. Pang, J.J., Chang, B., Hawes, N.L., Hurd, R.E., Davisson, M.T., Li, J., Noorwez, S.M., Malhotra, R., McDowell, J.H., Kaushal, S., Hauswirth, W.W., Nusinowitz, S., Thompson, D.A., and Heckenlively, J.R. (2005). Retinal degeneration 12 (rd12): A new, spontaneously arising mouse model for human Leber congenital amaurosis (LCA). Mol. Vis. 11, 152–162.
Poirier A.Campbell-Thompson M.Tang Q.Scott-Jorgensen M.Combee L.Loiler S.Crawford J.Song S.Flotte T.R.2004. Toxicology and biodistribution studies of a recombinant adeno-associated virus 2-α-1 antitrypsin vectorPreclinica243-51. Poirier, A., Campbell-Thompson, M., Tang, Q., Scott-Jorgensen, M., Combee, L., Loiler, S., Crawford, J., Song, S., and Flotte, T.R. (2004). Toxicology and biodistribution studies of a recombinant adeno-associated virus 2-α-1 antitrypsin vector. Preclinica 2, 43–51.
Provis J.M.Penfold P.L.Cornish E.E.Sandercoe T.M.Madigan M.C.2005. Anatomy and development of the macula: Specialisation and the vulnerability to macular degenerationClin. Exp. Optom.88269-281. Provis, J.M., Penfold, P.L., Cornish, E.E., Sandercoe, T.M., and Madigan, M.C. (2005). Anatomy and development of the macula: Specialisation and the vulnerability to macular degeneration. Clin. Exp. Optom. 88, 269–281.
Redmond T.M.Yu S.Lee E.Bok D.Hamasaki D.Chen N.Goletz P.Ma J.X.Crouch R.K.Pfeifer K.1998. Rpe65 is necessary for production of 11-cis-vitamin A in the retinal visual cycleNat. Genet.20344-351. Redmond, T.M., Yu, S., Lee, E., Bok, D., Hamasaki, D., Chen, N., Goletz, P., Ma, J.X., Crouch, R.K., and Pfeifer, K. (1998). Rpe65 is necessary for production of 11-cis-vitamin A in the retinal visual cycle. Nat. Genet. 20, 344–351.
Redmond T.M.Poliakov E.Yu S.Tsai J.Y.Lu Z.Gentleman S.2005. Mutation in key residues of RPE65 abolishes its enzymatic role as isomerohydrolase in the visual cycleProc. Natl. Acad. Sci. U.S.A.10213658-13663. Redmond, T.M., Poliakov, E., Yu, S., Tsai, J.Y., Lu, Z., and Gentleman, S. (2005). Mutation in key residues of RPE65 abolishes its enzymatic role as isomerohydrolase in the visual cycle. Proc. Natl. Acad. Sci. U.S.A. 102, 13658–13663.
Roman A.J.Schwartz S.B.Aleman T.S.Cideciyan A.V.Chico J.D.Windsor E.A.Gardner L.M.Ying G.S.Smilko E.E.Maguire M.G.Jacobson S.G.2005. Quantifying rod photoreceptor-mediated vision in retinal degenerations: Dark-adapted thresholds as outcome measuresExp. Eye Res.80259-272. Roman, A.J., Schwartz, S.B., Aleman, T.S., Cideciyan, A.V., Chico, J.D., Windsor, E.A., Gardner, L.M., Ying, G.S., Smilko, E.E., Maguire, M.G., and Jacobson, S.G. (2005). Quantifying rod photoreceptor-mediated vision in retinal degenerations: Dark-adapted thresholds as outcome measures. Exp. Eye Res. 80, 259–272.
Roman A.J.Boye S.L.Aleman T.S.Pang J.J.McDowell J.H.Boye S.E.Cideciyan A.V.Jacobson S.G.Hauswirth W.W.2007a. Electroretinographic analyses of Rpe65-mutant rd12 mice: Developing an in vivo bioassay for human gene therapy trials of Leber congenital amaurosisMol. Vis.131701-1710. Roman, A.J., Boye, S.L., Aleman, T.S., Pang, J.J., McDowell, J.H., Boye, S.E., Cideciyan, A.V., Jacobson, S.G., and Hauswirth, W.W. (2007a). Electroretinographic analyses of Rpe65-mutant rd12 mice: Developing an in vivo bioassay for human gene therapy trials of Leber congenital amaurosis. Mol. Vis. 13, 1701–1710.
Roman A.J.Cideciyan A.V.Aleman T.S.Jacobson S.G.2007b. Full-field stimulus testing (FST) to quantify visual perception in severely blind candidates for treatment trialsPhysiol. Meas.28N51-N56. Roman, A.J., Cideciyan, A.V., Aleman, T.S., and Jacobson, S.G. (2007b). Full-field stimulus testing (FST) to quantify visual perception in severely blind candidates for treatment trials. Physiol. Meas. 28, N51–N56.
Ross W.Lavina A.Russell M.Maberley D.2005. The correlation between height of macular detachment and visual outcome in macula-off retinal detachments of 97 days' durationOphthalmology1121213-1217. Ross, W., Lavina, A., Russell, M., and Maberley, D. (2005). The correlation between height of macular detachment and visual outcome in macula-off retinal detachments of 97 days' duration. Ophthalmology 112, 1213–1217.
Ross W.H.Kozy D.W.1998. Visual recovery in macula-off rhegmatogenous retinal detachmentsOphthalmology1052149-2153. Ross, W.H., and Kozy, D.W. (1998). Visual recovery in macula-off rhegmatogenous retinal detachments. Ophthalmology 105, 2149–2153.
Sandberg M.A.Brockhurst R.J.Gaudio A.R.Berson E.L.2005. The association between visual acuity and central retinal thickness in retinitis pigmentosaInvest. Ophthalmol. Vis. Sci.463349-3354. Sandberg, M.A., Brockhurst, R.J., Gaudio, A.R., and Berson, E.L. (2005). The association between visual acuity and central retinal thickness in retinitis pigmentosa. Invest. Ophthalmol. Vis. Sci. 46, 3349–3354.
Schocket L.S.Witkin A.J.Fujimoto J.G.Ko T.H.Schuman J.S.Rogers A.H.Baumal C.Reichel E.Duker J.S.2006. Ultrahigh-resolution optical coherence tomography in patients with decreased visual acuity after retinal detachment repairOphthalmology113666-672. Schocket, L.S., Witkin, A.J., Fujimoto, J.G., Ko, T.H., Schuman, J.S., Rogers, A.H., Baumal, C., Reichel, E., and Duker, J.S. (2006). Ultrahigh-resolution optical coherence tomography in patients with decreased visual acuity after retinal detachment repair. Ophthalmology 113, 666–672.
Sieving P.A.Caruso R.C.Tao W.Coleman H.R.Thompson D.J.Fullmer K.R.Bush R.A.2006. Ciliary neurotrophic factor (CNTF) for human retinal degeneration: Phase I trial of CNTF delivered by encapsulated cell intraocular implantsProc. Natl. Acad. Sci. U.S.A.1033896-3901. Sieving, P.A., Caruso, R.C., Tao, W., Coleman, H.R., Thompson, D.J., Fullmer, K.R., and Bush, R.A. (2006). Ciliary neurotrophic factor (CNTF) for human retinal degeneration: Phase I trial of CNTF delivered by encapsulated cell intraocular implants. Proc. Natl. Acad. Sci. U.S.A. 103, 3896–3901.
Simovich M.J.Miller B.Ezzeldin H.Kirkland B.T.McLeod G.Fulmer C.Nathans J.Jacobson S.G.Pittler S.J.2001. Four novel mutations in the RPE65 gene in patients with Leber congenital amaurosisHum. Mutat.18164. Simovich, M.J., Miller, B., Ezzeldin, H., Kirkland, B.T., McLeod, G., Fulmer, C., Nathans, J., Jacobson, S.G., and Pittler, S.J. (2001). Four novel mutations in the RPE65 gene in patients with Leber congenital amaurosis. Hum. Mutat. 18, 164.
Snyder R.O.Flotte T.R.2002. Production of clinical-grade recombinant adeno-associated virus vectorsCurr. Opin. Biotechnol.13418-423. Snyder, R.O., and Flotte, T.R. (2002). Production of clinical-grade recombinant adeno-associated virus vectors. Curr. Opin. Biotechnol. 13, 418–423.
Snyder R.O.Francis J.2005. Adeno-associated viral vectors for clinical gene transfer studiesCurr. Gene Ther.5311-321. Snyder, R.O., and Francis, J. (2005). Adeno-associated viral vectors for clinical gene transfer studies. Curr. Gene Ther. 5, 311–321.
Song S.Scott-Jorgensen M.Wang J.Poirier A.Crawford J.Campbell-Thompson M.Flotte T.R.2002. Intramuscular administration of recombinant adeno-associated virus 2 α-1 antitrypsin (rAAV-SERPINA1) vectors in a nonhuman primate model: Safety and immunologic aspectsMol. Ther.6329-335. Song, S., Scott-Jorgensen, M., Wang, J., Poirier, A., Crawford, J., Campbell-Thompson, M., and Flotte, T.R. (2002). Intramuscular administration of recombinant adeno-associated virus 2 α-1 antitrypsin (rAAV-SERPINA1) vectors in a nonhuman primate model: Safety and immunologic aspects. Mol. Ther. 6, 329–335.
Streilein J.W.2003. Ocular immune privilege: Therapeutic opportunities from an experiment of natureNature Rev.3879-889. Streilein, J.W. (2003). Ocular immune privilege: Therapeutic opportunities from an experiment of nature. Nature Rev. 3, 879–889.
Takahashi Y.Chen Y.Moiseyev G.Ma J.X.2006. Two point mutations of RPE65 from patients with retinal dystrophies decrease the stability of RPE65 protein and abolish its isomerohydrolase activityJ. Biol. Chem.28121820-21826. Takahashi, Y., Chen, Y., Moiseyev, G., and Ma, J.X. (2006). Two point mutations of RPE65 from patients with retinal dystrophies decrease the stability of RPE65 protein and abolish its isomerohydrolase activity. J. Biol. Chem. 281, 21820–21826.
Thompson D.A.Gyurus P.Fleischer L.L.Bingham E.L.McHenry C.L.Apfelstedt-Sylla E.Zrenner E.Lorenz B.Richards J.Jacobson S.G.Sieving P.A.Gal A.2000. Genetics and phenotypes of RPE65 mutations in inherited retinal degenerationInvest. Ophthalmol. Vis. Sci.414293-4299. Thompson, D.A., Gyurus, P., Fleischer, L.L., Bingham, E.L., McHenry, C.L., Apfelstedt-Sylla, E., Zrenner, E., Lorenz, B., Richards, J., Jacobson, S.G., Sieving, P.A., and Gal, A. (2000). Genetics and phenotypes of RPE65 mutations in inherited retinal degeneration. Invest. Ophthalmol. Vis. Sci. 41, 4293–4299.
Travis G.H.Golczak M.Moise A.R.Palczewski K.2007. Diseases caused by defects in the visual cycle: Retinoids as potential therapeutic agentsAnnu. Rev. Pharmacol. Toxicol.47469-512. Travis, G.H., Golczak, M., Moise, A.R., and Palczewski, K. (2007). Diseases caused by defects in the visual cycle: Retinoids as potential therapeutic agents. Annu. Rev. Pharmacol. Toxicol. 47, 469–512.
Yzer S.van den Born L.I.Schuil J.Kroes H.Y.van Genderen M.M.Boonstra F.N.van den Helm B.Brunner H.G.Koenekoop R.K.Cremers F.P.M.2003. A Tyr368His RPE65 founder mutation is associated with variable expression and progression of early onset retinal dystrophy in 10 families of a genetically isolated populationJ. Med. Genet.40709-713. Yzer, S., van den Born, L.I., Schuil, J., Kroes, H.Y., van Genderen, M.M., Boonstra, F.N., van den Helm, B., Brunner, H.G., Koenekoop, R.K., and Cremers, F.P.M. (2003). A Tyr368His RPE65 founder mutation is associated with variable expression and progression of early onset retinal dystrophy in 10 families of a genetically isolated population. J. Med. Genet. 40, 709–713.
Zaiss A.K.Muruve D.A.2008. Immunity to adeno-associated virus vectors in animals and humans: A continued challengeGene Ther.15808-816. Zaiss, A.K., and Muruve, D.A. (2008). Immunity to adeno-associated virus vectors in animals and humans: A continued challenge. Gene Ther. 15, 808–816.
Zolotukhin S.Potter M.Zolotukhin I.Sakai Y.Loiler S.Fraites T.J. Jr.Chiodom 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 vectorsMethods28158-167. Zolotukhin, S., Potter, M., Zolotukhin, I., Sakai, Y., Loiler, S., Fraites, T.J., Jr., Chiodom, V.A., Phillipsberg, T., Muzyczka, N., Hauswirth, W.W., Flotte, T.R., Byrne, B.J., and Snyder, R.O. (2002). Production and purification of serotype 1, 2, and 5 recombinant adeno-associated viral vectors. Methods 28, 158–167.
Information & Authors
Information
Published In
Copyright
Copyright 2008, Mary Ann Liebert, Inc.
History
Published ahead of print: 9 October 2008
Published online: 7 October 2008
Published in print: October 2008
Accepted: 22 August 2008
Received: 18 July 2008
Topics
Authors
Author Disclosure Statement
B.J.B., W.W.H., and the University of Florida have a financial interest in the use of AAV therapies, and own equity in a company (AGTC Inc.) that might, in the future, commercialize some aspects of this work. The University of Pennsylvania, the University of Florida, and Cornell University hold a patent on the described gene therapy technology (United States Patent 20070077228, “Method for Treating or Retarding the Development of Blindness”).
Metrics & Citations
Metrics
Citations
Export Citation
Export citation
Select the format you want to export the citations of this publication.
View Options
Get Access
Access content
To read the fulltext, please use one of the options below to sign in or purchase access.⚠ Society Access
If you are a member of a society that has access to this content please log in via your society website and then return to this publication.