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  • Successful arrest of photoreceptor and vision loss expands the therapeutic window of retinal gene therapy to later stages of disease.

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 of the United States of America (2015-10-16)
William A Beltran, Artur V Cideciyan, Simone Iwabe, Malgorzata Swider, Mychajlo S Kosyk, Kendra McDaid, Inna Martynyuk, Gui-Shuang Ying, James Shaffer, Wen-Tao Deng, Sanford L Boye, Alfred S Lewin, William W Hauswirth, Samuel G Jacobson, Gustavo D Aguirre
ABSTRACT

Inherited retinal degenerations cause progressive loss of photoreceptor neurons with eventual blindness. Corrective or neuroprotective gene therapies under development could be delivered at a predegeneration stage to prevent the onset of disease, as well as at intermediate-degeneration stages to slow the rate of progression. Most preclinical gene therapy successes to date have been as predegeneration interventions. In many animal models, as well as in human studies, to date, retinal gene therapy administered well after the onset of degeneration was not able to modify the rate of progression even when successfully reversing dysfunction. We evaluated consequences of gene therapy delivered at intermediate stages of disease in a canine model of X-linked retinitis pigmentosa (XLRP) caused by a mutation in the Retinitis Pigmentosa GTPase Regulator (RPGR) gene. Spatiotemporal natural history of disease was defined and therapeutic dose selected based on predegeneration results. Then interventions were timed at earlier and later phases of intermediate-stage disease, and photoreceptor degeneration monitored with noninvasive imaging, electrophysiological function, and visual behavior for more than 2 y. All parameters showed substantial and significant arrest of the progressive time course of disease with treatment, which resulted in long-term improved retinal function and visual behavior compared with control eyes. Histology confirmed that the human RPGR transgene was stably expressed in photoreceptors and associated with improved structural preservation of rods, cones, and ON bipolar cells together with correction of opsin mislocalization. These findings in a clinically relevant large animal model demonstrate the long-term efficacy of RPGR gene augmentation and substantially broaden the therapeutic window for intervention in patients with RPGR-XLRP.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-Opsin Antibody, Red/Green, Chemicon®, from rabbit
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Anti-G Protein Goα Antibody, clone 2A, clone 2A, Chemicon®, from mouse
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Anti-Rhodopsin Antibody, clone RET-P1, clone RET-P1, Chemicon®, from mouse
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Anti-Acetylated Tubulin antibody, Mouse monoclonal antibody produced in mouse, clone 6-11B-1, purified from hybridoma cell culture
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Anti-RPGR antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution