Long-term rescue of vision with antisense oligonucleotides in a mouse model of Usher syndrome

Abstract

Purpose : Retinitis pigmentosa (RP) affects 1 in 4000 individuals worldwide, yet there are no effective treatments available. Usher syndrome (Usher) is a form of RP that also includes hearing impairment. Transgenic mice with a mutation in the Ush1c gene (216A), which causes Usher in humans, have retinal dysfunction characteristic of RP, as well as profound hearing and vestibular deficits. We have previously shown that an ASO targeting the 216A mutation rescues hearing and balance in Usher mice. The purpose of this study was to test the effect of an ASO treatment regimen for RP in a mouse model of Usher.

Methods : Various of doses of 216A-targeted ASOs were delivered locally to the eye by intravitreal injection (IVI) in Usher and control-treated littermate mice. ASO localization in retinal cells after IVI was evaluated by immunohistochemistry (IHC) analysis. Ush1c gene and protein expression in the retina was determined by reverse transcription-polymerase chain reaction (RT-PCR) and IHC analyses, respectively. Visual function and retinal structures were evaluated by electroretinogram (ERG) and optical coherence tomography (OCT) imaging analyses, respectively.

Results : IHC analysis shows that IVI delivery of ASOs targets all regions and layers of the retina. RT-PCR analysis of retinal RNA isolated from ASO-treated Usher mice demonstrated a dose-dependent correction in Ush1c splicing. ERG and OCT analysis showed significant improvements in photoreceptor function and structure, respectively, after a single IVI treatment of ASO in neonatal and adult Usher mice compared to control mice. Repeated ASO treatments every three months over the course of a year sustained the therapeutic effect.

Conclusions : Our results show that ASOs delivered locally to the eye can effectively target Ush1c mutations in the retina and the potential for a long-term benefit to vision with ASO treatment in patients who carry this USH1C mutation. These results also demonstrate the efficacy of ASO therapeutics for the treatment of eye diseases in general.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.