Interventions and Treatments: Pre-Clinical

Summary

Our group has been involved in many pre-clinical experiments towards the development of potential treatments for patients. Experiments were performed to better understand changes to the retinal structure and function, and progression of retinal disease as a function of interventions. Gene augmentation therapy was evaluated in preclinical models of RPE65 (43,59,71,73,77,86,89,98,129,204), GUCY2D (74), MFRP (123), RPGR (109,123,126,142,154,176,206,210), BEST1 (187), RHO (193), and NPHP5 (217). Oral retinoid therapy was performed in preclinical models of Rpe65 (37,61,102). Other studies included AAV driven expression of GFP or VEGF (31,68), defining the effects of light on Rhodopsin mutant models (67), and evaluating melatonin in Rds mouse (42).

28 Publications On Pre-clinical Experimental Interventions Or Treatments

217. Aguirre GD, CIDECIYAN AV, Dufour VL, Garcia AR, Sudharsan R, Swider M, Nikonov R, Iwabe S, Boye SL, Hauswirth WW, Jacobson SG, Beltran WA. Gene therapy reforms photoreceptor structure and restores vision in NPHP5-associated Leber congenital amaurosis. Molecular Therapy, 29:2456-2468, 2021. [PubMed] [DOI]

210. Song C, Dufour VLL, CIDECIYAN AV, Ye GJ, Swider M, Newmark J, Timmers A, Robinson P, Knop DR, Chulay JD, Jacobson SG, Aguirre GD, Beltran WA, Shearman MS. Dose range finding studies with two RPGR transgenes in a canine model of X-linked retinitis pigmentosa treated with subretinal gene therapy. Human Gene Therapy, 31:743-755, 2020. [PubMed]

206. Dufour VLL, CIDECIYAN AV, Ye GJ, Song C, Timmers A, Habecker P, Pan W, Weinstein N, Swider M, Durham A, Ying GS, Robinson P, Jacobson SG, Knop DR, Chulay JD, Shearman MS, Aguirre GD, Beltran WA. Toxicity and efficacy evaluation of an AAV vector expressing codon-optimized RPGR delivered by subretinal injection in a canine model of X-linked retinitis pigmentosa. Human Gene Therapy, 31:253-267, 2020. [PubMed]

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]

193. CIDECIYAN AV, Sudharsan R, Dufour VL, Massengill MT, Iwabe S, Swider M, Lisi B, Sumaroka A, Marinho LF, Appelbaum T, Rossmiller B, Hauswirth WW, Jacobson SG, Lewin AS, Aguirre GD, Beltran WA. Mutation-independent rhodopsin gene therapy by knockdown and replacement with a single AAV vector. Proceedings of the National Academy of Sciences USA, 115:E8547-E8556, 2018. [PubMed] [PDF] [UPenn Press Release] [NEI Press Release] [Philadelphia Inquirer]

187. Guziewicz KE, CIDECIYAN AV, Beltran WA, Komaromy AM, Dufour VL, Swider M, Iwabe S, Sumaroka A, Kendrick BT, Ruthel G, Chiodo VA, Heon E, Hauswirth WW, Jacobson SG, Aguirre GD. BEST1 gene therapy corrects a diffuse retina-wide microdetachment modulated by light exposure. Proceedings of the National Academy of Sciences USA, 115:E2839-E2848, 2018. [PubMed] [PDF] [UPenn Press Release] [PNAS Podcast]

176. Beltran WA, CIDECIYAN AV, Boye SE, Ye G-J, Iwabe S, Dufour VL, Marinho LF, Swider M, Kosyk MS, Sha J, Boye SL, Peterson JJ, Witherspoon CD, Alexander JJ, Ying G-S, Shearman MS, Chulay JD, Hauswirth WW, Gamlin PD, Jacobson SG, Aguirre GD. Optimization of retinal gene therapy for X-linked retinitis pigmentosa due to RPGR mutations. Molecular Therapy, 25:1866-1880, 2017. [PubMed]

154. Beltran WA, CIDECIYAN AV, Iwabea S, Swider M, Kosyk MS, McDaida K, Martynyuka I, Ying G-S, Shaffer J, Deng W-T, Boye SL, Lewin AS, Hauswirth WW, Jacobson SG, Aguirre GD. Successful arrest of photoreceptor and vision loss expands the therapeutic window of retinal gene therapy to later stages of disease. Proceedings of the National Academy of Sciences USA 112:E5844-53, 2015. [PubMed] [NEI Press Release] [Penn Press Release] [PDF]

142. Beltran WA, CIDECIYAN AV, Lewin AS, Hauswirth WW, Jacobson SG, Aguirre GD. Gene augmentation for X-linked retinitis pigmentosa caused by mutations in RPGR. Cold Spring Harbor Perspectives in Medicine 5:a017392, 2015. [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]

126. Beltran WA, CIDECIYAN AV, Lewin AS, Iwabe1 S, Khanna H, Sumaroka A, Chiodo VA, Fajardo DS, Román AJ, Deng W-T, Swider M, Alemán TS, Boye SL, Genini S,Swaroop A, Hauswirth WW, Jacobson SG, Aguirre GD. Gene therapy rescues photoreceptor blindness in dogs and paves the way for treating human X-linked retinitispigmentosa. Proceedings of the National Academy of Sciences USA 109:2132-2137, 2012. [PubMed] [Penn News] [PDF]

123. Dinculescu A, Estreicher J, Zenteno JC, Aleman TS, Schwartz SB, Huang WC, Roman AJ, Sumaroka A, Li Q, Deng W-T, Min S-H, Chiodo VA, Neeley A, Liu X, Shu X, Matias-Florentino M, Buentello-Volante B, Boye SL, CIDECIYAN AV, Hauswirth WW, Jacobson SG. Gene therapy for retinitis pigmentosa caused by MFRP (Membrane-type Frizzled Related Protein) mutations: Human phenotype and preliminary proof-of-concept. Human Gene Therapy 23:367-376, 2012. [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]

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]

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]

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]

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]

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]

74. Williams ML, Coleman JE, Haire SE, Aleman TS, CIDECIYAN AV, Sokal I, Palczewski K, Jacobson SG, Semple-Rowland SL. Lentiviral expression of retinal Guanylate Cyclase-1 (RetGC1) restores vision in an avian model of childhood blindness. PLoS Medicine 3:e201, 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]

68. Lebherz C, Maguire AM, Auricchio A, Tang W, Aleman TS, Wei Z, Grant R, CIDECIYAN AV, Jacobson SG, Wilson JM, Bennett J. Nonhuman primate models for diabetic ocular neovascularization using AAV2-mediated overexpression of vascular endothelial growth factor. Diabetes 54:1141-1149, 2005. [PubMed]

67. CIDECIYAN AV, Jacobson SG, Aleman TS, Gu D, Pearce-Kelling SE, Sumaroka A, Acland GM, Aguirre GD. In vivo dynamics of retinal injury and repair in the rhodopsin mutant dog model of human retinitis pigmentosa. Proceedings of the National Academy of Sciences USA 102:5233-5238, 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]

42. Liang F-Q, Aleman TS, Yang Z, CIDECIYAN AV, Jacobson SG, Bennett J. Melatonin delays photoreceptor degeneration in the rds/rds mouse. Neuroreport 12:1011-1014, 2001. [PubMed]

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]

31. Bennett J, Maguire AM, CIDECIYAN AV, Schnell M, Glover E, Anand V, Aleman TS, Chirmule N, Gupta AR, Huang Y, Gao G-P, Nyberg WC, Tazelaar J, Hughes J, Wilson JM, Jacobson SG. Stable transgene expression in rod photoreceptors after recombinant adeno-associated virus-mediated gene transfer to monkey retina. Proceedings of the National Academy of Sciences USA 96:9920-9925, 1999. [PubMed] [PDF]

Last updated August 15, 2020