Antisense oligonucleotide therapy rescues disruptions in organization of exploratory movements associated with Usher syndrome type 1C in mice

Abstract

Usher syndrome, Type 1C (USH1C) is an autosomal recessive inherited disorder in which a mutation in the gene encoding harmonin is associated with multi-sensory deficits (i.e., auditory, vestibular, and visual). USH1C (Usher) mice, engineered with a human USH1C mutation, exhibit these multi-sensory deficits by circling behavior and lack of response to sound. Administration of an antisense oligonucleotide (ASO) therapeutic that corrects expression of the mutated USH1C gene, has been shown to increase harmonin levels, reduce circling behavior, and improve vestibular and auditory function. The current study evaluates the organization of exploratory movements to assess spatial organization in Usher mice and determine the efficacy of ASO therapy in attenuating any such deficits. Usher and heterozygous mice received the therapeutic ASO, ASO-29, or a control, non-specific ASO treatment at postnatal day five. Organization of exploratory movements was assessed under dark and light conditions at two and six-months of age. Disruptions in exploratory movement organization observed in control-treated Usher mice were consistent with impaired use of self-movement and environmental cues. In general, ASO-29 treatment rescued organization of exploratory movements at two and six-month testing points. These observations are consistent with ASO-29 rescuing processing of multiple sources of information and demonstrate the potential of ASO therapies to ameliorate topographical disorientation associated with other genetic disorders.

Sexually dimorphic organization of open field behavior following moderate prenatal alcohol exposure

“…For example, the vestibular system might be developmentally sensitive to PAE. Genetic models of vestibular pathology have been observed to spare stop clustering in the open field behavior under light conditions (Donaldson et al, 2018). In contrast, the current study observed that PAE male rats exhibited weaker stop clustering across samples.…”

“…Two minutes after the rat was placed on the open field, four consecutive 5‐min samples of activity were captured for analysis. The 2‐min delay was based on previous work demonstrating that rodents exhibit markers of organized open field behavior including home base establishment (e.g., circling, grooming, and rearing) within 2 min of exposure to a novel environment (Banovetz et al, 2021; Donaldson et al, 2018). Ethovision XT 13 (Noldus) was used to digitize body position in the open field at five frames per second.…”

Antisense Oligonucleotides for the Treatment of Inner Ear Dysfunction

“…An investigation of the organization of exploratory movements in these mice was used to assess spatial organization in both dark and light settings. Typically, mice utilize a combination of environmental as well as self-movement cues as they explore and these activities were found to be disrupted in Usher mice and recovered in Usher mice treated with ASO to correct Ush1c splicing [79].…”

Usher Syndrome: Genetics and Molecular Links of Hearing Loss and Directions for Therapy

“…This partial correction by ASO increases harmonin expression, improves the morphology and structure of stereocilia, leading to a rescue of auditory and vestibular responses in Ush1c mice. This shows that early-treated mice respond better due to an age threshold for effective drug delivery (Lentz et al, 2013;Vijayakumar et al, 2017;Donaldson et al, 2018). Similarly, Ponnath et al (2018) reported restoration of OHC and IHC in Ush1c mice by ASO-29 treatment.…”