Rescue of peripheral vestibular function in Usher syndrome mice using a splice-switching antisense oligonucleotide
| Autor: | Michelle L. Hastings, Frank Rigo, Sarath Vijayakumar, Timothy A. Jones, Francine M. Jodelka, Frederic Depreux, Jennifer J Lentz |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Retinal degeneration Vestibular evoked myogenic potential Usher syndrome Sensory system Cell Cycle Proteins Biology Retina 03 medical and health sciences Mice Hearing Genetics medicine otorhinolaryngologic diseases Animals Molecular Biology Genetics (clinical) Balance (ability) Vestibular system Retinal Degeneration General Medicine Articles Oligonucleotides Antisense medicine.disease Vestibular Evoked Myogenic Potentials Cytoskeletal Proteins Disease Models Animal 030104 developmental biology Vestibule Mutation Systemic administration Evoked Potentials Auditory sense organs Vestibule Labyrinth Carrier Proteins Neuroscience Usher Syndromes |
| Zdroj: | Human molecular genetics. 26(18) |
| ISSN: | 1460-2083 |
| Popis: | 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 in mice 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 was made. Here, we measured vestibular sensory evoked potentials (VsEPs) to directly assess vestibular function in Usher mice. We report that VsEPs are absent or abnormal in Usher mice, indicating profound loss of vestibular function. Strikingly, Usher mice 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 of mice 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 a mouse model of USH1C and reveal the potential for using antisense technology to treat vestibular dysfunction. |
| Databáze: | OpenAIRE |
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