Reversing Hearing Loss | TS Digest


     Stained marginal cells of the stria vascularis of the cochlea.

Steel’s team imaged marginal cells (red) of the cochlea, which maintain EP necessary for hearing, in a Spns2 mutant mouse. Normal cellular function is shown in green, and the blue patches show the breakdown of cells associated with deteriorated hearing.

Elisa Martelletti

Hundreds of genes influence hearing loss, and although hearing aids and cochlear implants offer some reprieve, deafness reversal options do not exist.¹ In an early step to ameliorate one type of inner ear dysfunction, a recent study reported that timely activation of a gene associated with early onset deafness reversed hearing loss in mice.² This proof of concept approach may one day lead to a solution for people with hearing loss attributed to genetic causes.

“Most people tend to think that any neurological disease like deafness, or any sort of problem with brain function at all, represents an irreversible step, and there’s no way of going back,” said Karen Steel, a geneticist at King’s College London who led this work. 

To study genetic hearing loss, Steel and her team mutated spinster homolog 2 (Spns2), a gene associated with early onset hearing loss and subsequent deficiency in endocochlear potential (EP), which acts as an inner ear battery by providing the electrical force for normal auditory function.³ They designed the mutation such that they could reverse it with a single tamoxifen injection. 

Mice lacking Spns2 experienced rapid hearing loss within two weeks after birth. “This is a window of opportunity to try to activate the gene,” explained Steel. The researchers injected mice with tamoxifen at 14 to 28 days post birth. Using scalp electrodes, they measured brainstem responses to various sound frequencies before and after the injections. 

They saw gradual hearing improvement in their mice after gene reactivation. The team also noted improved cell morphology in the cochlea, which generates EP, and higher EP levels in these mice compared to their counterparts that lacked Spns2. “This was really the first time that they had any realistic reasonable hearing level,” said Steel. Lastly, earlier reactivation in mice showed more effective sound registration at normal frequencies. 

These findings elucidate the developmental timeframe of intervention in this specific type of hearing loss. Jeffrey Holt, a neuroscientist at Harvard Medical School who was not involved in the study, said, “The field of biological therapies for hearing loss is really in its infancy, but I think there’s great potential.” 

Steel next plans to explore whether other forms of genetic deafness and mechanisms of pathology in hearing loss can also be reversed.

References

  1. Ingham NJ, et al. PLoS Biol. 2019;17(4):e3000194.
  2. Martelletti E, et al. PNAS. 2023;120(34):e2307355120.
  3. Chen J, et al. PLoS Genet. 2014;10(10):e1004688.

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