Hearing: genetics and stem cells

03 April 2018

Interview with

Jeff Holt, University of Harvard Medical School

Hearing loss will affect 1 in 6 of us. Could some cutting edge therapies help? Georgia Mills heard from Boston Medical School Professor Jeff Holt.

Jeff - Some of the techniques we’re working on in my lab, and others are also interested in this, are gene therapies. So if we can identify a gene that has a mutation that leads to hearing loss, the goal would be to introduce the correct DNA that doesn’t have a mutation, a healthy gene in other words, reintroduce that back into the sensory cells of the inner ear and thereby restore function.

Georgia - How would you go about doing that?

Jeff - The strategy we’ve been using is to engineer a viral vector. We take a virus that’s known as adeno-associated virus; this is present in most human populations. It doesn’t cause disease but we can engineer it, remove the viral genes and then insert any gene of interest, any DNA sequence we’d like to put into the ear. Viruses are particularly good at carrying DNA sequences into the cells so the virus will do its job, carry the DNA that we’ve inserted into the sensory cell of the ear and then the ear knows what to do with that gene to make the correct protein and restore function.

Georgia - Just as an example: if the DNA didn’t know how to code for the hair cells properly, you would get a virus to sneak in the right segment of DNA; that would then go into where it’s meant to be and start being used by the cell to start building a hair cell properly?

Jeff - Exactly.

Georgia - That sounds brilliant, so does it work?

Jeff - So far, we’ve tested it in mouse models and, remarkably, it does work. We can take a deaf mouse and allow them to recover sensitivity to sounds as soft as a whisper.

Georgia - Can this intervention happen at any age of the mouse or does it have to happen while it’s still developing?

Jeff - That really depends on the specific gene we’re targeting. Some genes don’t turn on until late in development or only at mature stages, some are critical at very early stages of development so there may be a window, a therapeutic window of opportunity which we would want to intervene before that window is closed, and it really has to be dissected out on a gene-by-gene basis. In some cases, we’ve seen that it’s required to put the gene back in at the early stages, but in other cases we think we can do it later. It has not been tested in humans yet, but that’s something that we’re working towards, and there’s growing interest in trying to move this to the clinic.

Georgia - What barriers do you need to cross before we can give this a go?

Jeff - We need to identify the suitable patients to target for a clinical trial. We also need to confirm that there’s enough safety data; we want to make sure we’re not making the situation any worse or making anybody sick with side effects and so forth. Once we’ve got those two bits confirmed then we need to find the funding to be able to do this. But, I think if we pull those three together, we should be able to begin a clinical trial for gene therapy in humans for hearing loss.

Georgia - Oh right! So as far as we know there are not massive scientific barriers, at least, that would stop us from attempting this?

Jeff - That’s right. I think the science is showing that it should be possible.

Georgia - That’s the genetic side of things. What about using stem cells?

Jeff - There are a number of approaches for using stem cells to try to regenerate the inner ear. Some of them currently are to take a stem cell in the lab in a dish and grow it it into an inner ear organoid. An organoid is something that would resemble or look like the inner ear containing the sensory hair cells, as well as the neurons, that would connect the hair cells, the sensory cells, to the brain. Those might be used to test or screen for other drugs, but eventually they could possibly be used a transplantation situation where you could transplant a whole organoid into a deaf ear and maybe recover function. I think that’s a little further off.

Some of the other approaches that are being explored at the moment are to see if we can reawaken the native stem cellness of cells that are present in the ear and cause them to differentiate and become new sensory hair cells.

Georgia - How hard is it to build a mini ear in a dish then? Have you managed it yet?

Jeff - Yes, we have managed it. We start by using stem cells that are pluripotent, meaning they could become any number of different cell types. And we provide a couple of the correct factors that cause them to head towards an inner ear cell type and the we leave them alone to let them follow their own path. Just giving them a little bit of push at the beginning leads them down the right path and we eventually, after 30 to 60 days, and end up with something that looks like an inner ear.

Georgia - And then you can use this to test various drugs on to see how they would work in a human ear without risking a human’s ear?

Jeff - Exactly. It’s a great model system to be able to screen pharmaceutical compounds, as well as some of the gene therapy compounds I mentioned earlier.

Georgia - In terms of getting stem cells into an ear, we’re far away from this, but what are the challenges involved in getting something like this to work?

Jeff - There are still a few challenges. We need to be able to make a correct cell type, and if we introduce that correct cell then into the ear, it needs to be integrated into a complex organ so that it’s oriented properly, it’s stimulated properly, and responds to sound, and so that it’s corrected properly with the neurons that transmit information to the brain.

Georgia - And are there any risks with a technique this?

Jeff - Well, with stem cells, this hasn’t really been done in humans too much yet. There are always risks that the stem cells could differentiate into some unwanted cell type.

Georgia - Would this be either something you don’t want or could it become cancerous as well?

Jeff - That’s always a possibility. In the inner ear, luckily, there are no native cancers in the inner ear, but we would want to be cautious about putting some new cell type in the ear that could differentiate into something pathogenic.

Georgia - So perhaps genetic therapy could reduce genetic deafness down the line, and if we can make sure the stem cells turn into the right cells and don’t become cancerous, they could one day help people who do wish to restore their hearing.

Bella’s hearing was restored to her through an operation, after she was re-diagnosed with what we know to be a curable condition. She described her first experience hearing music again.

Bella - When I’d had those operations, I did have this extraordinary experience of listening to music for the first time without any artificial amplification and it did absolutely blow my mind. It was extraordinary because it was about six weeks after the second operation and a friend of mine had got tickets - a rather cultured friend of mine had got tickets to go and see the Berlin Philharmonic playing Schubert and Haydn, neither of whom I really knew anything about.

Simon Rattle walked to the podium and he raised his baton, and then it was just like something completely sort of all body experience. It was like the sound didn’t just enter my ears, it was like standing under a waterfall. It was a kind of complete physical experience. It was like it was resetting my cells or something, it was absolutely extraordinary. It just poured through me and was like a sort of fuse box came back on again, it was properly mind blowing.


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