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Edward Averbukh, Ron Ofri, Elisha Gootwine, Raaya Ezra-Elia, Hen Honig, Alexander Rosov, Esther Yamin, Alexey Obolensky, William Hauswirth, Eyal Banin; RECOVERY OF VISUAL FUNCTION FOLLOWING GENE THERAPY IN A LARGE ANIMAL MODEL OF CNGA3 ACHROMATOPSIA. Invest. Ophthalmol. Vis. Sci. 2013;54(15):2708.
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© ARVO (1962-2015); The Authors (2016-present)
Recently, we reported on novel hereditary dayblindness in sheep caused by a mutation in the CNGA3 gene (Reicher et al., Genomics 95:101-104, 2010). Since mutations in this gene can also cause achromatopsia in humans, we decided to use these sheep as a cone-enriched, large animal model to evaluate safety and efficacy of CNGA3 gene therapy.
The unique anatomical features of the ovine eye required development of a surgical procedure for subretinal delivery. Subsequently, different types of Adeno-Associated Viral (AAV) vectors carrying the intact human or mouse CNGA3 gene were delivered unilaterally into the subretinal or vitreal space of affected sheep. Animals were electrophysiologically and behaviorally assessed preoperatively and 2 and 6 months post-operatively. A sub-group of animals were also tested 12 months after treatment. Cone function was measured by electroretinography (ERG) following light adaptation (10 min., 30 cd/m2). Responses to photopic flash and flicker (10-80Hz) stimuli were recorded at 4 intensities (1-10 cd x sec/m2). Behavioral assessment included scotopic and photopic maze testing under standardized conditions. Passage times and number of collisions were recorded. Age-matched normal and day-blind sheep were similarly assessed as controls.
Cone function as measured by ERG was significantly depressed in affected sheep prior to surgery. Following surgery, there was significant improvement in eyes treated by either the human or the mouse CNGA3 gene under control of the red-green Opsin promoter. Behaviorally, there were no differences between dayblind and normal controls in scotopic testing, but dayblind animals failed to navigate the maze under photopic conditons. Following delivery of either the human or the mouse CNGA3-carrying vector, the ability of previously dayblind sheep to navigate the photopic maze without collisions improved dramatically, approaching that of normal controls. The electrophysiological and behavioral improvement in operated sheep persisted for at least 1 year post-op without affecting the animals' health.
AAV-mediated gene therapy improves cone-dependant visual function in CNGA3 dayblind sheep, with a good safety profile. The long-term electrophysiological and behavioral improvement in this naturally-occurring large animal model may pave the way to application of similar treatment in human achromatopsia patients.
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