RPE65-associated LCA


Leber congenital amaurosis (LCA) refers to severe visual deficits with an onset in infancy and caused by inherited conditions affecting the structure or function of the photoreceptors across the retina. LCA is genetically heterogeneous with mutations known in >20 genes to date. About 10% of LCA is caused by mutations in RPE65. RPE65 encodes the retinoid isomerase of the canonical visual (retinoid) cycle that recycles the visual chromophore 11-cis-retinal between RPE and photoreceptor cells. Mutations in RPE65 block the visual cycle and result in a congenitally inadequate supply of chromophore to both rod and cone photoreceptors. The result is a loss of light sensitivity. There is also a progressive retinal degeneration that causes the loss of photoreceptors. Many aspects of the human RPE65-associated LCA has been described by our group over the last 2 decades (see refs below: 37,41,69,80,86,88,95,98,101,109,129,130,143,146,148,155).

There are naturally occurring dogs with RPE65 mutations (43,71,73,86,109,129,204), and also naturally occurring and genetically engineered mouse models (37,59,61,89,98,102,109,110,122).

Around 1999, our group was involved in two distinct approaches to treating the RPE65 defect. One approach was the use of an oral artificial retinoid to bypass the blocked natural visual cycle. Proof of concept studies in mice (37,61,102) led to a multi-center clinical trial funded by QLT, and our group showed that rod-photoreceptor mediated night vision could be improved with an oral retinoid within a matter of days (146).

A second approach to treating RPE65-LCA was to use gene augmentation therapy. Dramatic results demonstrating improvements in both rod-based night vision and cone-based day vision were performed in dogs (43,71,73,86,109) and mice (59,89,98,109,129). Safety studies were performed (73,77).

From 2007 to date, our group has been involved in a single-center clinical trial supported by the National Eye Institute to perform gene augmentation trial in patients with RPE65-LCA. Measurements of light sensitivity in patients who received subretinal gene therapy showed never-before-seen 100,000-fold improvements occurring in a matter of days (97,98,104,106,109,111,122,129,143,148).


33 Publications On RPE65-Associated LCA

204. Gardiner KL, CIDECIYAN AV, Swider M, Dufour VL, Sumaroka A, Komaromy AM, Hauswirth WW, Iwabe S, Jacobson SG, Beltran WA, Aguirre GD. Long-term structural outcomes of late-stage RPE65 gene therapy. Molecular Therapy, 28:266-278, 2020. [PubMed] [Penn Press Release] [EurekAlert]

155. Jacobson SG, CIDECIYAN AV, Huang WC, Sumaroka A, Nam HJ, Sheplock R, Schwartz SB. Leber congenital amaurosis: Genotypes and retinal structure phenotypes. Advances in Experimental Medicine and Biology 854:169-75, 2016. [PubMed]

148. Jacobson SG, CIDECIYAN AV, Roman AJ, Sumaroka A, Schwartz SB, Heon E, Hauswirth WW. Improvement and decline in vision with gene therapy in childhood blindness. New England Journal of Medicine 372:1920-1926, 2015. [PubMed] [Editorial] [NEI Press Release] [Penn Press Release] [Science Now]

146. Jacobson SG, CIDECIYAN AV, Aguirre GD, Roman AJ, Sumaroka A, Hauswirth WW, Palczewski K. Improvement in vision: a new goal for treatment of hereditary retinal degenerations. Expert Opinion on Orphan Drugs 3:563-575, 2015. [PubMed]

143. CIDECIYAN AV, Aguirre GK, Jacobson SG, Butt OH, Schwartz SB, Swider M, Roman AJ, Sadigh S, Hauswirth WW. Pseudo-fovea formation after gene therapy for RPE65-LCA. Investigative Ophthalmology & Visual Science 56:526-537, 2015. [PubMed]

133. CIDECIYAN AV, Jacobson SG, Beltran WA, Hauswirth WW, Aguirre GD. Reply to Townes-Anderson: RPE65 gene therapy does not alter the natural history of retinal degeneration. Proceedings of the National Academy of Sciences USA 110:E1706, 2013. [PubMed]

130. Roman AJ, CIDECIYAN AV, Schwartz SB, Olivares MB, Heon E, Jacobson SG. Intervisit variability of visual parameters in Leber congenital amaurosis caused by RPE65 mutations. Investigative Ophthalmology & Visual Science 54:1378-1383, 2013. [PubMed]

129. CIDECIYAN AV, Jacobson SG, Beltran WA, Sumaroka A, Swider M, Iwabe S, Roman AJ, Olivares MB, Schwartz SB, Komaromy AM, Hauswirth WW, Aguirre GD. Human retinal gene therapy for Leber congenital amaurosis shows advancing retinal degeneration despite enduring visual improvement. Proceedings of the National Academy of Sciences USA 110:E517-25, 2013. [PubMed] [NEI News Brief] [Penn News] [Commentary] [WOC Lecture] [PDF]

122. 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 J-J, Erger KE, Olivares MB, Mullins CL, Swider M, Kaushal S, Feuer WJ, Iannaccone A, Fishman GA, Stone EM, Byrne BJ, Hauswirth WW. Gene therapy for Leber congenital amaurosis caused by RPE65 mutations: Safety and efficacy in fifteen children and adults followed up to three years. Archives of Ophthalmology 130:9-24, 2012.[PubMed]

111. Banin E, Bandah-Rosenfeld D, Obolensky A, CIDECIYAN AV, Aleman TS, Marks-Ohana D, Sela M, Boye S, Sumaroka A, Roman AJ, Schwartz SB, Hauswirth WW, Jacobson SG, Sharon D. Molecular anthropology meets genetic medicine to treat blindness in the north african Jewish population: Human gene therapy initiated in Israel. Human Gene Therapy, 21:1749-1757, 2010. [PubMed]

110. Caruso RC, Aleman TS, CIDECIYAN AV, Roman AJ, Sumaroka A, Mullins CL, Boye SL, Hauswirth WW, Jacobson SG. Retinal disease in Rpe65-deficient mice: comparison to human Leber congenital amaurosis due to RPE65 mutations. Investigative Ophthalmology & Visual Science, 51:5304-5313, 2010. [PubMed]

109. CIDECIYAN AV. Leber congenital amaurosis due to RPE65 mutations and its treatment with gene therapy. Progress in Retinal and Eye Research, 29:398-427, 2010.[PubMed]

106. CIDECIYAN AV, Hauswirth WW, Aleman TS, Kaushal S, Schwartz SB, Boye SL, Windsor EAM, Conlon TJ, Sumaroka A, Pang J, Roman AJ, Byrne BJ, Jacobson SG. Human RPE65 gene therapy for Leber congenital amaurosis: persistence of early visual improvements and safety at 1 year. Human Gene Therapy, 20:999-1004, 2009.[PubMed] [Reprint]

104. CIDECIYAN AV, Hauswirth WW, Aleman TS, Kaushal S, Schwartz SB, Boye SL, Windsor EAM, Conlon TJ, Sumaroka A, Roman AJ, Byrne BJ, Jacobson SG. Vision 1 year after gene therapy for Leber’s congenital amaurosis. New England Journal of Medicine, 361:725-727, 2009. [PubMed] [Reprint] [Free Text in PubMed Central]

102. Maeda T, CIDECIYAN AV, Maeda A, Golczak M, Aleman TS, Jacobson SG, Palczewski K. Loss of cone photoreceptors caused by chromophore depletion is partially prevented by the artificial chromophore pro-drug, 9-cis-retinyl acetate. Human Molecular Genetics, 18:2277-2287, 2009. [PubMed]

101. Jacobson SG, Aleman TS, CIDECIYAN AV, Roman AJ, Sumaroka A, Windsor EAM, Schwartz SB, Heon E, Stone EM. Defining the residual vision in Leber congenital amaurosis caused by RPE65 mutations. Investigative Ophthalmology & Visual Science, 50:2368-2375, 2009. [PubMed]

98. CIDECIYAN AV, Aleman TS, Boye SL, Schwartz SB, Kaushal S, Roman AJ, Pang J-j, Sumaroka A, Windsor EAM, Wilson JM, Flotte TR, Fishman GA, Heon E, Stone EM, Byrne BJ, Jacobson SG, Hauswirth WW. 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 USA, 105: 15112-15117, 2008. [PubMed] [PDF]

97. Hauswirth WW, Aleman TS, Kaushal S, CIDECIYAN AV, Schwartz SB, Wang L, Conlon TJ, Boye SL, Flotte TR, Byrne BJ, Jacobson SG. 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, 19:979-990, 2008. [PubMed]

95. Jacobson SG, CIDECIYAN AV, Aleman TS, Sumaroka A, Windsor EAM, Schwartz SB, Heon E, Stone EM. Photoreceptor layer topography in children with Lebercongenital amaurosis caused by RPE65 mutations. Investigative Ophthalmology & Visual Science, 49:4573-4577, 2008. [PubMed]

89. Roman AJ, Boye SL, Aleman TS, Pang J-J, McDowell JH, Boye SE, CIDECIYAN AV, Jacobson SG, Hauswirth WW. Electroretinographic analyses of Rpe65-mutant rd12 mice: developing an in vivo bioassay for human gene therapy trials of Leber congenital amaurosis. Molecular Vision, 13:1701-1710, 2007. [PubMed] [PDF]

88. Jacobson SG, Aleman TS, CIDECIYAN AV, Heon E, Golczak M, Beltran WA, Sumaroka A, Schwartz SB, Windsor EAM, Wilson JM, Aguirre GD, Stone EM, Palczewski K. Human cone photoreceptor dependence on RPE65 isomerase. Proceedings of the National Academy of Sciences USA, 104:15123-15128, 2007. [PubMed] [PDF]

87. Roman AJ, CIDECIYAN AV, Aleman TS, Jacobson SG. Full-field stimulus testing (FST) to quantify visual perception in severely blind candidates for treatment trials. Physiological Measurement, 28:N51-56, 2007. [PubMed]

86. Aguirre GK, Komáromy AM, CIDECIYAN AV, Brainard DH, Alemán TS, Roman AJ, Avants BB, Gee JC, Korczykowski M, Hauswirth WW, Acland GM, Aguirre GD, Jacobson SG. Canine and human visual cortex intact and responsive despite early retinal blindness from RPE65 mutation. PLoS Medicine, 4:e230, 2007. [PubMed] [PDF]

80. Jacobson SG, CIDECIYAN AV, Aleman TS, Sumaroka A, Schwartz SB, Windsor EAM, Roman AJ, Heon E, Stone EM, Thompson DA. RDH12 and RPE65, visual cycle genes causing Leber congenital amaurosis, do not share disease expression. Investigative Ophthalmology & Visual Science 48:332-338, 2007. [PubMed]

77. 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. Safety in nonhuman primates of ocular AAV2-RPE65, a candidate treatment for blindness in Leber congenital amaurosis. Human Gene Therapy 17:845-58, 2006. [PubMed]

73. Jacobson SG, Acland GM, Aguirre GD, Aleman TS, Schwartz SB, CIDECIYAN AV, Zeiss CJ, Komaromy AM, Kaushal S, Roman AJ, Windsor EAM, Sumaroka A, Pearce-Kelling SE, Conlon TJ, Chiodo VA, Boye SL, Flotte TR, Maguire AM, Bennett J, Hauswirth WW. Safety of recombinant adeno-associated virus type 2-RPE65 vector delivered by ocular subretinal injection. Molecular Therapy 13:1074-1084, 2006. [PubMed]

71. 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. 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, 2005. [PubMed]

69. Jacobson SG, Aleman TS, CIDECIYAN AV, Sumaroka A, Schwartz SB, Windsor EAM, Traboulsi EI, Heon E, Pittler SJ, Milam AH, Maguire AM, Palczewski K, Stone EM, Bennett J. Identifying photoreceptors in blind eyes due to RPE65 mutations: Prerequisite for human gene therapy success. Proceedings of the National Academy of Sciences USA 102:6177-6182, 2005. [PubMed] [PDF]

61. Aleman TS, Jacobson SG, Chico JD, Scott ML, Cheung AY, Windsor EAM, Furushima M, Redmond TM, Bennett J, Palczewski K, CIDECIYAN AV. Impairment of the transient pupillary light reflex in Rpe65-/- mice and humans with Leber congenital amaurosis. Investigative Ophthalmology & Visual Science 45:1259-1271, 2004. [PubMed]

59. Dejneka NS, Surace EM, Aleman TS, CIDECIYAN AV, Lyubarsky A, Savchenko A, Redmond TM, Tang W, Wei Z, Rex TS, Glover E, Maguire AM, Pugh EN Jr, Jacobson SG, Bennett J. In utero gene therapy rescues vision in a murine model of congenital blindness. Molecular Therapy, 9:182-188, 2004. [PubMed]

43. 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. Gene therapy restores vision in a canine model of childhood blindness. Nature Genetics 28:92-95, 2001. [PubMed]

41. Poehner WJ, Fossarello M, Rapoport AL, Aleman TS, CIDECIYAN AV, Jacobson SG, Wright AF, Danciger M, Farber DB. A homozygous deletion in RPE65 in a small Sardinian family with autosomal recessive retinal dystrophy. Molecular Vision 6:192-198, 2000. [PubMed] [PDF]

37. van Hooser JP, Aleman TS, He Y-G, CIDECIYAN AV, Kuska V, Pittler SJ, Stone EM, Jacobson SG, Palczewski K. Rapid restoration of visual pigment and function with oral retinoid in a mouse model of childhood blindness. Proceedings of the National Academy of Sciences USA 97:8623-8628, 2000. [PubMed] [PDF]

Last updated January 15, 2020