Rescue of peripheral vestibular function in Usher syndrome mice using a splice-switching antisense oligonucleotide

Usher syndrome type 1C (USH1C/harmonin) is associated with profound retinal, auditory and vestibular dysfunction. We have previously reported on an antisense oligonucleotide (ASO-29) that dramatically improves auditory function and balance behavior inmice homozygous for the harmonin mutation Ush1c c.216G > A following a single systemic administration. The findings were suggestive of improved vestibular function; however, no direct vestibular assessment wasmade. Here, we measured vestibular sensory evoked potentials (VsEPs) to directly assess vestibular function in Ushermice. We report that VsEPs are absent or abnormal in Ushermice, indicating profound loss of vestibular function. Strikingly, Ushermice receiving ASO-29 treatment have normal or elevated vestibular response thresholds when treated during a critical period between postnatal day 1 and 5, respectively. In contrast, treatment ofmice with ASO-29 treatment at P15 was minimally effective at rescuing vestibular function. Interestingly, ASO-29 treatment at P1, P5 or P15 resulted in sufficient vestibular recovery to support normal balance behaviors, suggesting a therapeutic benefit to balance with ASO-29 treatment at P15 despite the profound vestibular functional deficits that persist with treatment at this later time. These findings provide the first direct evidence of an effective treatment of peripheral vestibular function in amouse model of USH1C and reveal the potential for using antisense technology to treat vestibular dysfunction.