Curated by UCL

Gene therapy takes on genetic hearing loss

Most of us take our ability to hear for granted. Yet for at least one child in every 1000 births, the sound of a bird chirping or car alarm sounding is but a figment of their imagination.[1] Childhood hearing loss can have a significant impact on a child’s academic and social life and, around half of the time, can be traced back to an abnormality in certain genes. Faults in one of the genes encoding an important group of proteins called connexins, found in the cochlea of our inner ears, are particularly common in children with severe hearing loss. This has led scientists to question whether the replacement or ‘supplementation’ of these faulty connexin genes, by a process known as gene therapy, could help restore hearing in this form of genetic hearing loss. Now, for the first time, a lab group in Japan has used this technique to treat mice with connexin-related hearing loss whilst in the womb, successfully enabling them to hear when they are born.

The cochlea is a fundamental structure of our inner ears involved in enabling us to hear. This is where sound vibrations from the middle ear are transformed into electrical signals by special receptor cells called hair cells, before being passed to the brain. The activation of hair cells in the presence of a sound is a complex process but essentially involves the movement of positively charged potassium ions (K+) from the endolymph (a solution found in one of the compartments of the cochlea) into the hair cells, causing them to become activated and send electrical signals to the brain: see Figure 1. Once the sound has passed, K+ ions are then released from the hair cells and recycled back into the endolymph, ready to begin the whole process again.[2]

 

Figure 1

Figure 1: Simplified illustration of the movement of potassium (K+) ions and the location of connexins in the endolymph-containing compartment of the cochlea.

This is where connexin proteins are thought to come in. These proteins are found between the ‘non-hair’ cells which line the endolymph-containing compartment of the cochlea within structures called gap junctions. Since gap junctions are responsible for allowing the movement of ions between cells, it seems logical to suggest that connexins are important to hearing by permitting K+ ions to be recycled back into the endolymph.[2]

The necessity of connexins to the integrity of hair cells and the ability to hear has been demonstrated previously in both humans and mice. For instance, mice generated without functional connexin proteins display severe hearing loss and show significant hair cell degeneration within the first few months of life.[3] Genetic studies in humans with severe hearing loss have also found faults in genes encoding various connexin proteins known to be housed in the cochlea.

Based on such findings, Toru Miwa and colleagues from Kumamoto University in Japan set out to test whether they could replace faulty connexin genes with healthy ones, as a way of treating connexin-related hearing loss. To do so, they injected healthy versions of connexin genes into the embryos of connexin deficient mice; specifically targeting the region of the embryo destined to become the left ear.[1] This would allow for a comparison between the left, treated ears and the right, non-treated ears of the mice. They then waited with anticipation for the mice to be born.

The wait was well worth it. Post-birth, Miwa’s team found functional connexin proteins expressed in the left ears of the mice, while the right, untreated ears remained deficient. What was more exciting was that the mice could hear with their left ears, but not their right.[1] This was determined using a method similar to the one used in human hearing tests; by measuring the level of brain activity in response to sounds delivered to each ear. While low or non-existent levels of brain activity were recorded when the mice were using their right ears to hear, sounds delivered to their left ears produced significant brain activity, even at low sound levels. The gene therapy to replace the faulty connexin genes had been a success and had restored the hearing of these mice!

Miwa and colleagues’ results provide significant evidence to suggest that connexin-related genetic hearing loss may be treated using gene therapy. Although this is so far only true for mice with the condition, the idea of using healthy versions of faulty genes to treat genetic hearing loss is a highly exciting prospect and could be applicable to other genes related to this condition, thus widening its use. Maybe one day, children with genetic hearing loss won’t have to imagine what the world around them sounds like and can be as annoyed as the rest of us at that car alarm going off around the corner.

References

  1. T. Miwa, R Minoda, M Ise, et al, Mouse otocyst transuterine gene transfer restores hearing in mice with connexin 30 deletion-associated hearing loss, Molecular Therapy. 21, pp. 1142–1150, 2013.
  2. H Zhao, T Kikuchi, A Ngezahayo, et al, Gap junctions and cochlear homeostasis, Journal of Membrane Biology. 209, pp. 177–186, 2006.
  3. B Teubner, V Michel, J Pesch, et al, Connexin30 (Gjb6)-deficiency causes severe hearing impairment and lack of endocochlear potential, Human Molecular Genetics 12, pp. 13–21, 2003.

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