“Effects of Antisense Oligonucleotide Treatment on Photoreceptor Function in a mouse Model of Usher Syndrome”

Usher syndrome (USH) is the most common cause of inherited deaf‐blindness. Depending on the type (I, II, or III), hearing impairment and vestibular dysfunction can be variable, but all Usher patients exhibit a progressive loss of vision due to retinitis pigmentosa (RP). Usher syndrome type 1 (USH1) is responsible for 35 – 45% of all Usher cases and is characterized by severe to profound hearing impairment and vestibular dysfunction at birth, as well as, the development of RP in early adolescence. 6–8% of USH1 are caused by mutations in the USH1C gene, which encodes the protein Harmonin. Harmonin has been shown to play an important role in the development and function of auditory hair cells in the cochlea; however, its role in the retina is unknown. Our lab has produced a knock‐in mouse model containing the human USH1C c.216G>A splicing mutation (216A) responsible for USH1 in Acadian patients of south Louisiana. These mice have profound hearing impairment, vestibular dysfunction, loss of visual function and slow retinal degeneration similar to patients. Recently, antisense oligonucleotides (ASOs) targeting the 216A mutation in these mice have been shown to enhance correct Ush1c gene and Harmonin protein expression, and be efficacious in rescuing hearing and vestibular function when administered by intraperitoneal injection (systemic). However, only marginal improvement in visual function was observed; possibly due to an insufficient concentration of the ASO in the eye. The purpose of this study was to evaluate visual function after an intravitreal (local) ASO treatment. Rod and cone photoreceptor function was evaluated by scotopic and photopic electroretinogram (ERG) analysis, respectively, in ASO‐treated 216AA mutant and littermate control mice. An increase in scotopic a‐wave amplitude was observed within 3 months of ASO treatment in 216A mutant mice compared with control littermates, indicating an early improvement in rod function. This improvement was observed when the mice were treated at 1, 3 or 6 months of age, suggesting a large temporal window for successful intervention between adolescence and adulthood. An analysis of photopic ERGs showed no differences in untreated 216AA mutant and control littermates, suggesting cone function is not affected in early stages of disease. These data demonstrate the potential of ASOs for the treatment of retinitis pigmentosa associated with Usher syndrome. Support or Funding Information This research was supported by grant #1359140 through the National Science Foundation