Gene Therapy Holds Potential in Otoferlin-Related Hearing Loss

DB-OTO, an investigational gene therapy, showed promising efficacy in initial results from the phase 1/2 CHORD trial (NCT05788536), with 10 children who were born with genetic hearing loss showing meaningful hearing improvements. Jay T. Rubinstein, MD, PhD, Virginia Merrill Bloedel Professor of Otolaryngology and Bioengineering and Director, Bloedel Hearing Research Center, University of Washington School of Medicine, and a CHORD clinical trial investigator, discussed the mechanisms of otoferlin gene–related hearing loss and the potential of DB-OTO in this patient population.

This transcript has been lightly edited; captions were auto-generated.

Transcript

Can you explain the mechanism(s) of how variants of the otoferlin gene cause hearing loss, and how DB-OTO works to improve hearing in these patients?

One of the reasons this is the first congenital hearing loss to be treated by gene therapy is because in otoferlin mutations, the inner ear is completely normal, with a very important exception: it's missing the otoferlin protein. And the otoferlin protein is necessary for synaptic transmission between the inner hair cells and the auditory nerve. But in every other way, the cochlea is completely normal, and what the gene therapy does is provide the missing protein.

How quickly after administration of the gene therapy did patients start to hear? Based on the patients treated thus far, is there a “normal” trajectory for patients gaining hearing?

I've only personally treated 1 of the patients in the clinical trial. The clinical trial shows that many patients show a response within about a month of the treatment, and that was true for my patient as well. One month after treatment, they had hearing that they did not have before, and they had an auditory brainstem response that they didn't have before, which is a physiologic test that's used to assess hearing in babies.

Were there any side effects?

[There were] none directly attributable to the drug. The surgery to place the gene therapy is similar to cochlear implant surgery, and a variety of people had postoperative issues that were brief, that are very commonly seen in a population of people undergoing cochlear implant surgery, but nothing specifically related to the gene therapy itself.

What are the next steps in the trial?

At this point, what we know is that some children who've received this can hear at remarkably high levels within months of treatment. That is, they have hearing thresholds that are normal or near normal at multiple frequencies. Others don't do quite as well, and 1 person got no response at all. We've seen quite a bit of variability of outcome that we're not able to explain yet because there's not enough patients and they haven't been followed long enough.

At the end of the day, what we need to know is, how does this treatment compare to the current standard of care, which is a cochlear implant? And we're not in a position to make that comparison yet, but it's only a matter of time before we will be able to make that comparison. And basically, when you say, "Where does it go from here?" the answer is, more patients and more time for follow up of the existing patients.

Does this include a wider age range of participants?

That's correct, and it also will involve a larger range of testing. In young children, the most important thing you can measure is the level of their hearing. How loud a sound can they detect? But it's very challenging to measure speech understanding in a 2-year-old. There are ways we can do that, but those ways are not amenable to a clinical trial like this. It's either [we] see what happens when they're 5 years old, which is when we have the first really good tools for assessing speech discrimination, or it's having more older children who have normal speech and language. These would be, typically, people who got a cochlear implant in 1 ear when they were babies, they developed normal speech and language, and then they got gene therapy in the other ear. When they're of an age where we can do really detailed testing of their hearing ability, that's when we're going to find out just how normal or just how good can this treatment do in terms of surpassing the benefits of a cochlear implant?

We will have a population of people that have a cochlear implant in 1 ear and gene therapy in the other ear, and we'll actually get to compare them. They'll have different histories—the cochlear implant will have been in since they were very young, and their brain will have developed with the cochlear implant. But we will begin to do the kinds of testing that really can answer for us, "Is this better than a cochlear implant?" Certainly, the data we have right now looks really promising that that could be the case.

Is it known yet whether this is a 1-time therapy or a treatment that will have to be repeated?

It is a really good question. We do not know the answer to yet—there are theoretical reasons to believe that the treatment is permanent, and there are theoretical reasons to believe why it might not be. And the answer is, we'll find out when we find out. But at the moment, we just don't know yet.