Gene therapy partially reverses deafness in mice!

An exciting new study published in Science Translational Medicine has successfully used a gene therapy technique to regenerate partial hearing in deaf mice. It’s at once an important step toward treatment of genetic forms of deafness in humans, and more general proof that gene therapy is well on its way to being a powerful part of modern medicine.

It’s important to understand the causes of the particular type of genetic deafness addressed in this study. A simple defect in the gene for transmembrane channel-like protein 1 (TMC1) prevents the tiny, crucial hairs of the cochlea from being able to create electrical impulses at the appropriate time, stimulating the auditory cortex of the brain and causing the perception of sound. This specific problem is reportedly responsible for some 4-8% of cases of genetic deafness — but importantly it does not otherwise impede the development or overall health of the cochlear hairs themselves.

Adeno-associated virus 2

They’re intact and mostly ready to go, lacking only the working version of this one critical signaling protein. Since gene therapy is all about making very specific genes and proteins available to cells, that’s specifically the sort of problem that gene therapy is best suited to address.

This particular therapy works by loading a healthy version of the gene for TMC1 into the genetically defanged genome of a highly effective virus called adeno-associated virus 2 (AAV2), using the virus as the insertion vehicle for the therapeutic gene. Scientists inject the virus into the ear, and from there it does precisely what it evolved to do in the first place: insert the DNA it carries into lots and lots of host cells.

Once inside the cochlear hair cells, this single-stranded DNA genome hijacks the local cellular machinery to make itself double-stranded (and thus much more durable) and enter the host cell’s nucleus. From here, the tiny medical/viral genome can act as a template for the cell to start making healthy, working copies of the TMC1 protein — and since that’s all these cochlear hair cells needed to start working properly, they slowly start to do just that.

An electron micrograph of some cochlear hair cells.

The hair cells are ready and able to get the new healthy proteins into place on their own outer membranes, since of course they were supposed to be making and placing the healthy proteins all along. Finally handed some healthy TMC1 by this therapy, the cells happily incorporate it into their normal cellular functioning.

Interestingly, one of the most medically inconvenient facts about cochlear hair cells — that, "like most neurons, they do not regrow if damaged "— helps out in this case. If the cochlear hair cells were dividing on a regular basis, they would leave the newly inserted therapeutic genes behind every time they split; since these hair cells do not divide, the inserted genome remains in the nucleus, producing the needed proteins potentially for the rest of the hair cell’s lifetime.

Not all forms of deafness, or disease in general, are this easily addressed with gene therapy. That’s why quick, cheap genome sequencing and the personalized medicine it will allow will be so crucial to getting the most out of these sorts of techniques. When your therapies work on the level of individual genes, your understanding of the causes of disease have to be just as detailed.

Harvard professor Jeffrey Holt, one of the lead researchers on this study, said that he “can envision patients with deafness having their genome sequenced and a tailored, precision medicine treatment injected into their ears to restore hearing.”