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Comment by petesergeant | Hacker News Reader

More information on the approach: https://www.uniqure.com/programs-pipeline/huntingtons-diseas...

> AMT-130 consists of an AAV5 vector carrying an artificial micro-RNA specifically tailored to silence the huntingtin gene, leveraging our proprietary miQURE™ silencing technology. The therapeutic goal is to inhibit the production of the mutant protein (mHTT)

and the actual announcement: https://uniqure.gcs-web.com/news-releases/news-release-detai...

> 75% slowing of disease progression as measured by Unified Huntington’s Disease Rating Scale (p=0.003)

> 60% slowing of disease progression as measured by Total Functional Capacity (p=0.033)

> 88% slowing of disease progression as measured by Symbol Digit Modalities Test (p=0.057)

> 113% slowing of disease progression as measured by Stroop Word Reading Test (p=0.0021)

> 59% slowing of disease progression as measured by Total Motor Score (p=0.1741)

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It always seemed that an mRNA treatment was going to be the way forward for treating HD, speaking as an HD widower.

And here my government is actively working to suppress mRNA therapies because of fucking politics. Fuck them.

This isn't an mRNA treatment. The m in mRNA stands for "messenger", not micro. mRNA covid vaccines don't mess with the genome anything like this treatment does, and indeed, this treatment is much more dangerous than any vaccine would be.

Why does it have to be delivered through brain surgery?

Guessing: bypassing the blood-brain barrier.

I’m assuming the viral vector can’t pass the blood-brain barrier.

But it doesn’t take 10+ hours to surgically get a virus across the blood-brain barrier, right?

The video specifies that the drug is infused over 8-10 hours. Probe placement - again, as depicted in the video, because I don’t see a real methods section - should take about 1-2 hours. The video isn’t clear if this is interactive MRI or just a preop scan that is then loaded into a stereotactic navigation system in a regular operating room, but the former would add another hour at least. MRI is not fast.

The major hurdle of current gene therapies is delivery to the tissue where the defective gene product is causing damage. For instance lipid nanoparticles are only being used to deliver gene therapies to the liver, because if you inject them they just end up there and not much anywhere else. In this case they are using an virus called "adeno asociated virus 5" (AAV5), which does not naturally infect the brain AFAIK. The blood brain barrier (basically just extra impermeable blood vessels), as well as other immunological features in brain tissue, evolved specifically to keep the brain as unaffected as possible from anything bad going on in the body, seeing as any infection/poisoning of the brain is varying degrees of catastrophic and would easily kill you in the ancestral environment.

I don't know the details of why AAV5 in particular is their vector of choice in this case, but for whatever reason thats what they've gone with. AFAIK there are no viral or other vectors that consistently infect all brain tissue when injected/ingested, so maybe that's just the best option available. Anyways, it seems that in order to get it to the actual brain tissue that is damaged by the huntington protein (all of it? One particular area?), the best way is to inject it where it needs to go. If you could just pump it into the CSF that would perhaps make things a little bit more tolerable, seeing as you could then just do a spinal tap and inject it that way, but apparently that doesn't work. Or maybe a generalized AAV5 infection has more side effect then targeted injections. Just speculating here.

I guess it needs to get across the blood-brain barrier. But that shouldn’t take 10+ hours of surgery, I don’t think.

Surgery can be slow, and brain surgery doubly so.

The brain is slightly elastic, so you'd want to advance a needle glacially slowly (microns/second) into it so it ends up at the right position. The injection itself is also done slowly (microliters/minute) so you don't cause pressure damage.

They might also do some intraoperative imaging (some ORs have MRI or CT machines), which slows things down, and of course there's tons of cleaning and repair work afterward.

>AFAIK there are no viral or other vectors that consistently infect all brain tissue when injected/ingested

Rabies?

The brain-blood barrier typically only allows small, non-polar molecules to pass through into the brain, which complicates a lot of neuro/psych treatments.

Thanks for sharing this information. Do you (or anyone else here) know if these trends might be expected based on how the treatment works? For example, given than the treatment is only injected into certain parts of the brain, could we expect that some aspects of the disease will be treated better than others?

What does 113% slowing mean? I thought if the speed is x then 80% slowing means the speed is now 0.2x

Perhaps it means the effects of the disease are actually reversed?

"The data also shows the treatment is saving brain cells. Levels of neurofilaments in spinal fluid – a clear sign of brain cells dying – should have increased by a third if the disease continued to progress, but was actually lower than at the start of the trial."

What do those progression numbers mean in terms of outlook? For example, if someone is treated before showing symptoms (as they know they inherit it) is the progression slowing enough to give them a normal life expectancy and quality of life?

It’s covered in the article

>It means the decline you would normally expect in one year would take four years after treatment, giving patients decades of "good quality life", Prof Sarah Tabrizi told BBC News.

>The first symptoms of Huntington's disease tend to appear in your 30s or 40s and is normally fatal within two decades – opening the possibility that earlier treatment could prevent symptoms from ever emerging.

I don’t think this quite answers the curiosity of whether starting treatment e.g. at birth would virtually eliminate morbidity, or whether it only slows the decline once it has started.

Consider that the disease typically manifests in your 30s — does this mean it would begin 4x later (and thus basically never manifest), or that your 15 year progressive decline from ~35-50 would take 4x longer (giving you a normal lifespan, albeit perhaps with some limitations in your later years)?

To me, as an HD widower, it would have meant that my dead wife would had lived until 2043 and had a decade more of a mostly normal life.

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