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Comment by Noaidi | Hacker News Reader

This is good news, but I still have concerns.

Otoferlin [1] uses calcium as a cofactor. These mutations happen for a reason. The enzyme is not only located in the ear, but also in the brain and bone marrow [2].

Will there be repercussions if the virus leaves the local area when the therapy is injected?

These OTOF mutation have their highest expression in the Turkish population. Many people with other variations of this gene only experience deafness when they have a fever[3]. So in my opinion, I would like to see ten year outcomes before celebrating.

[1] https://www.uniprot.org/uniprotkb/Q9HC10/entry

[2] https://www.proteinatlas.org/ENSG00000115155-OTOF/tissue

[3] https://www.frontiersin.org/journals/cell-and-developmental-...

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The Regeneron press release mentions that the therapy includes a hair cell specific regulator for the gene:

https://investor.regeneron.com/news-releases/news-release-de...

That of course doesn't rule out problems, but the treatment doesn't naively turn on the protein production either.

There are a lot of risks with retroviral genetic therapy. However, there are a lot of upsides. I think what we need most, is to gain as much knowledge as possible, to ensure we can treat anything untoward as a result.

In terms of 'leaving the local area', there was a recent treatment intended to be done on one eye first, just in case it did not go as planned. It spread to the other eye:

https://www.cam.ac.uk/research/news/gene-therapy-injection-i...

Viral vector DNA was detected in the anterior segment, retina and optic nerve of the untreated eye. The unexpected visual improvement observed in the untreated eyes could therefore reflect the interocular diffusion of rAAV2/2-ND4. Further investigations are needed to confirm these findings and whether other mechanisms are contributing to this bilateral improvement.

Seeing as the eye was directly injected, it's unclear how it spread. Blood, likely.

Yes, some of the vector was likely cleared from the AH and exposed the contra lateral eye

Patients with fever induced hearing loss regardless of OTOF mutations were specifically excluded (see inclusion criteria on clinical trials.gov for NCT05788536).

With regard to your point about shedding or systemic exposure. If non functional copies of OTOF in the other tissues expressing the gene were to be replaced by functional copies, what is the concern? How would that negatively impact patients? Doesn’t seem like this would/should be a concern.

Also, mutations don’t have to be teleologically beneficial to occur and persist. They can persist because they are not fatal nor do they impair reproductive competence.

Good to have concerns, but if I was deaf I'd weigh them based on how much I want to hear and discuss the risks with my doctor.

Personally I think I would want to hear once in my life, even if it meant a potentially shorter life.

I'm glad the Trump admin prioritized this.

This was not a political decision. These kind of accelerated paths have been available for years for a wide variety of therapies.

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