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Gene therapy breakthrough for hearing loss

A team of international researchers have used a new gene therapy technique to restore hearing in mice with a genetic form of deafness that is similar to a type found in people (called DFNB9). Our Translational Research Manager, Dr Carina Santos, tells us more about their work.

There are three main types of treatments that could, in the future, restore hearing: drug-based treatments, stem cell therapies and gene therapies. All have the potential to change the lives of the millions of people who live with hearing loss.

What is DFNB9?

Most cases of hereditary deafness are caused by mutations (changes) in the DNA of our genes. DFNB9 is a form of hereditary deafness caused by a mutation in the OTOF gene, which produces a protein called otoferlin. Otoferlin is a component of the sound-sensing hair cells, found in the inner ear; it is needed for hair cells to send sound information from the ear along the auditory nerve to the brain. When the OTOF gene is mutated, otoferlin does not work correctly and so sound information cannot reach the brain. As a consequence, people with mutations in this gene are profoundly deaf.

How the researchers restored hearing in mice

While studying ways to correct the mutated OTOF gene to restore hearing in people, an international team of researchers from France and the USA used mice which had been genetically engineered to lack the gene for otoferlin (the gene is known as Otof in mice) as a model of human DFNB9 deafness. Using these mice, they tested ways to deliver healthy copies of the Otof gene to hair cells in a fully-developed, mature cochlea (inner ear).

To do this, they used a gene therapy method involving viruses – tiny particles of DNA (or a related molecule called RNA) and protein that can infect cells and integrate their DNA into that of the cell (an example of a virus you might be familiar with is the common cold virus). By modifying the genes contained within the DNA of a virus, scientists can engineer them to carry specific genes into specific cells to correct the effects of mutations. Particular viruses can only infect certain types of cell, so by selecting the virus type carefully, and controlling how and where it gets into the body, researchers can ensure that it only infects the cells they want it to – in this case, cells in the inner ear.

Here, the researchers ‘packaged’ healthy copies of the Otof gene into a type of virus called an adeno-associated virus, or AAV, which has shown promise in being able to infect inner ear cells. It also doesn’t cause a significant immune response, and is not known to cause disease, both of which are important features for a gene therapy virus! However, there is one significant problem with AAV – the amount of DNA that can be packaged into it is quite small, and many human genes are too large to fit into it, including the OTOF/Otof gene. So to get round this problem, the researchers engineered two different AAV viruses, one containing the first half of the gene, and the other containing the second half. Each half had a ‘signal’ built into it that would allow them to join back together once they were inside the cell.

Image of an AAV particle virus

They injected these viruses into the cochlea of the DFNB9 model mice, both before and after hearing onset (which occurs when the cochlea is fully mature). Unlike people, who are born with a fully mature cochlea, and therefore hear from birth, mice only start to hear several days after they are born, when their cochlea fully matures. This allows researchers to test regenerative therapies like gene therapy at different stages of cochlear development.

Using their AAV gene therapy, the team were able to deliver healthy full copies of the Otof gene to more than half of the hair cells in the cochlea. They were also able to show that this restored communication between the ear and the brain, as the mice could hear. If the gene therapy was given before the cochlea had fully developed, it prevented the mice from becoming deaf, but even more crucially, administration of the same gene therapy after hearing onset in the mice was able to restore their hearing – and the mice were still able to hear 20 weeks later (mice live on average for 2 years).

Why this is study important

In people, hearing onset occurs before we are born – we are born with a fully mature cochlea. This means we need to develop treatments that can restore hearing after the cochlea has fully developed. This study shows that it is possible to use gene therapy to restore hearing even after the cochlea is fully mature. Also importantly, the researchers have shown that this technique can be used for genes that are too big to fit into one virus particle, which increases the number of hearing loss genes that this approach could be used to treat. And now the researchers have shown that it works in one type of hearing loss, other genes can be tested in this system to see if it can correct mutations in other hearing loss-causing genes, and ultimately move towards developing gene therapies based on this technique that can be tested in people.

Researchers all over the world are currently investigating ways to restore hearing, whether through drugs, stem cells or gene therapy. There are already drugs and gene therapies to restore hearing being tested in people in clinical trials. If successful, these therapies will transform the lives of the millions of people who nowadays live with hearing loss and would like to be able to hear again.

Further information

This research was published earlier this month in the journal PNAS.

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