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Russell J Amato, Robert Rosencrans, Francine M Jodelka, Anthony J Hinrich, Nicolas G Bazan, Frank Rigo, Michelle L Hastings, Jennifer J. Lentz; Early effects of antisense oligonucleotide treatment on photoreceptor function and retinal structure in a mouse model of Usher Syndrome. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):5452.
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© ARVO (1962-2015); The Authors (2016-present)
Type 1 Usher syndrome (USH) is characterized by profound hearing impairment and vestibular dysfunction at birth and the development of retinitis pigmentosa in early adolescence. 6-8% of USH1 cases are caused by mutations in the USH1C gene, which encodes the protein harmonin. Our lab has produced a knock-in mouse model containing the human USH1C c.216G>A splicing mutation (216A) and these mice have a loss of visual function and slow retinal degeneration similar to human Usher syndrome. Recently, antisense oligonucleotides (ASOs) targeting the 216A mutation have been shown to enhance correct Ush1c splicing and translation and be efficacious in rescuing hearing and vestibular function when administered systemically. Only marginal improvement in visual function in these mice was observed, however; possibly due to an insufficient concentration of the ASO in the eye. The purpose of this study was to test the effects of ASO treatment on Ush1c expression, visual function and retinal structure when delivered locally to the eye in 216AA mice.
Various doses of 216A-targeted ASOs were delivered locally to the eye by intravitreal injection (IVI) in neonatal and adult 216AA mutant and control-treated littermate mice. The expression of Ush1c splice variants in the retina was determined by reverse transcription-polymerase chain reaction (RT-PCR). Visual function and retinal structures were evaluated by electroretinogram (ERG) and optical coherence tomography (OCT) imaging analyses, respectively.
RT-PCR analysis of Ush1c splice variants in retinal tissues isolated from 216AA mice treated with various doses of ASOs demonstrated a dose-responsive correction in Ush1c splicing. ERG and OCT analysis showed significant improvements in visual function (a-wave maximum amplitude) and retinal structures (photoreceptor outer nuclear layer and inner/outer segment thickness), respectively, within 3 months of a single IVI treatment of ASOs in neonatal 216AA mice. Treatment of adult mice had no effect on photoreceptor function or retinal structures shortly after treatment.
Our results show that ASOs delivered locally to the eye can effectively target Ush1c mutations in the retina. These results suggest the therapeutic potential of early ASO intervention to improve gene expression, photoreceptor structure and function in Usher syndrome.
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