A research group investigated the use of gene therapy for treating inherited hearing loss.
Around the world, there are roughly 466 million people who suffer from hearing loss, 60% of which can be attributed to a genetic cause. Over 120 genes are connected to hereditary deafness, many of which are variants present only in small populations. Currently, there are no treatments for hearing loss that have been established using cell, gene therapy, or pharmacological methods. The predominant treatment for deafness at this time includes cochlear implants and sound amplification.
A research team from Tel Aviv University (Tel Aviv, Israel) examined the possibility of gene therapy for hearing loss. Previous studies have shown that variants in SYNE4 (Spectrin Repeat Containing Nuclear Envelope Family Member 4) cause hearing loss in humans. Mice specifically bred to lack SYNE4 display a loss and degeneration of nuclei on outer hair cells, which is critical in auditory function. They were used for this study to model the impacts of gene therapy on those lacking SYNE4, and are referred to as Syne4-knockout mice.
Using a synthetic adeno-associated virus (AAV), researchers injected Syne4 into the inner ears of neonatal mice. These viruses are often used when investigating gene therapeutics, as they don’t cause any adverse immune reactions. AAV9-PH.B was used in this case, as it had been previously shown to effectively transfer genetic material to inner and outer hair cells in mice, as well as non-human primates.
Using an operating binocular to carefully locate the posterior-semicircular canal (PSCC), the inner ear canals of neonatal mice were injected with the AAV. After recovery, a combination of auditory testing, cued fear conditioning, and balance assessment was carried out with the treated mice. It was found that behavioral responses associated with auditory cues were corrected for those that had been injected with the virus. Upon completion of the behavioral tests, it was observed that there was an improvement in the survival and structure of outer hair cells in the neonatal mice. These results suggest that humans dealing with inherited deafness due to mutations with SYNE4 could be treated using gene therapy.
There were several limitations to this study, the most significant of which was the use of mice as a model species. The timeline in which deafness is evident varies between species, as the hearing of Syne4-knockout mice declined much more quickly. Humans with SYNE4 variants often exhibit deafness after birth. This would impact the timeline in which gene therapy can be carried out. Additionally, although there were no adverse effects observed in the mice after treatment, it would be important to closely observe any physiological responses before moving onto human trials.
This study highlights the importance of developing gene therapy for hearing loss, and the potential approach that could be used to develop a treatment. However, there are many uncertainties due to the gene variants that can cause deafness and the differences between the physiology of mice and humans. More experiments should be developed to better understand the relationship between genes and hearing loss, and the potential therapy that can treat inherited deafness.
Source: Taiber S, Cohen R, Yizhar-Barnea O, Sprinzak D, Holt JR, Avraham KB. Neonatal AAV gene therapy rescues hearing in a mouse model of SYNE4 deafness. EMBO Mol Med. 2020 Dec 22:e13259. doi: 10.15252/emmm.202013259. Epub ahead of print. PMID: 33350593.
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