[maxall4]

I'm honestly quite shocked that the physicians/scientists involved would choose to use an AAV for a brain-targeted gene therapy. There is just so much data demonstrating that these vectors are quite immunoreactive: most of the approved gene therapies based on AAVs carry black box labels for liver failure caused by an immune reaction to the viral capsid. Admittedly, AAVs are the most derisked vector for gene therapies, but infusing them directly into someone's brain and expecting nothing bad to happen is, in my view, crazy.

[fgimenez]

[Note that I work in this field and have co-founded a CNS AAV company]

This isn't the correct takeaway. AAV are one of the most complex drug modalities and carry considerable risk when used incorrectly. This story is tragic and violates pretty much every ethical consideration for a clinician researcher. Especially ones that are treating children of desperate parents.

That said, AAV are one of the most powerful delivery mechanism we have to deliver gene therapies to the brain. Uniqure has shown the first efficiacious treatment of Huntington's disease with intraparenchymal delivery of AAV5, Zolgensma is a brain targeted AAV9 to treat SMA, Kebilidi is an intraparenchymal AAV2 that treats AADC deficiency.

The general approach should be to keep dose as low as possible and minimally expose the periphery. AAV9 at large doses delivered intrathecally without standardized immunosuppression is simply insane.

[vibrio]

I agree with you that AAV is clearly a useful tool but at times the low levels of self discipline and scientific rigor that the field has applied to dosing is disappointing at best and scary at times. This includes use of other vector types such as by bluebirdbio and even the Jesse Gelsinger tragedy. “If a little is good then more is better” is a crazy and lazy way to apply and optimize these technologies.

[refurb]

Zolgensma acts on the peripheral motor neurons not the CNS

[timy2shoes]

Another compounding issue is that they had to package the vector into two parts, which then have to both infect the same cell to get any effect. Which means you have to at least double the dose to get similar coverage compared to a single AAV vector (and actually more than double). Seems like a easy recipe for liver toxicity. Which is why most companies doing AAV therapy either target the liver or the eye (where AAV doesn't escape to the liver).

I feel like the parents were not well enough informed of the risks, and the PI rushed the therapy to be famous. Not the first time this has happened, and not the last, sadly.

[arjie]

These are all fair complaints, but DB-OTO works the same way for the otoferlin-related hearing loss: it's packaged on two viral AAV vectors. It's given to much smaller babies, though there are some Chinese reports of a similar gene therapy in teens. So it's clearly not just the dual-vector but also the target etc.

[gus_massa]

IANAMD. I remember something about that virus in the brain are super bad, and there is an additional protection to avoid virus and random substances entering the brain. They injected the virus in the medula, that is inside the protection membrane. In an ideal case, is it a good idea?