Gene-silencing tool shows promise as a future therapy against prion diseases

https://news.mit.edu/2024/charmed-collaboration-creates-therapy-candidate-fatal-prion-diseases-0627

by gmays • 2 years ago

222 68 2 years ago

news.mit.edu

The Wired deep dive on the couple whose lab this came from is worth a read: https://www.wired.com/story/sleep-no-more-crusade-genetic-ki...

gumby• 2 years ago

Thank you for that. I'm normally uninterested in the "people behind the story" articles but this one was very good and I'm glad to have read it.

dyauspitr2• 2 years ago

There’s a decent TED talk as well by the woman involved (Vallabh)

gushogg-blake• 2 years ago

Does this affect infectious prion diseases as well, or just the genetic ones? Article makes it sound like everyone has the prion protein gene, so not sure what the different etiologies are. My understanding was that prions were just self-replicating proteins with no biological mechanisms involved, but apparently it's more complex than that.

Terr_• 2 years ago

It sounds as if this is mostly a case where the initial infection is a matter of time, and the goal is to stop it from occurring:

CHARMs, however, work further upstream, turning off the gene that codes for the faulty protein so that the protein never gets made in the first place. [...] In a person who hasn’t yet developed symptoms, removing the protein should prevent disease altogether.

That said, it may still be relevant as a helpful therapy for someone already infected, if the accidental production of "fresh" prions--happening in parallel in all cells--is a much bigger problem than an existing prion floating around and catalyzing neighbors:

Testing in mice showed that ZFP-guided CHARMs could eliminate more than 80 percent of the prion protein in the brain, while previous research has shown that as little as 21 percent elimination can improve symptoms.

thatoneguy• 2 years ago

Both the communicable and noncommunicable prion diseases still require a particular protein (and typically protein isoform since some folks are resistant to vCJD) to be present so I think this would work on both forms. That said, someone doesn’t normally now they have a prion disease until it’s probably too late to do anything about it.

throwawaymaths• 2 years ago

Possibly.

A corrections: a prion (the disease agent) is believed to be a self replicating protein fold, so it needs a source protein ("prion protein", aka PrP, one word) to feed the folding.

Now, although the evidence is pretty solid that the fold is the infectious agent, there's a lot of unanswered questions: we can try to make prions in the lab but iiuc no one has made a fiber of PrP in the lab without seeding from an infectious sample that itself was infectious.

Moreover, a lot of related Alzheimer's research has come under intense scrutiny recently[0], so much so that the viral hypothesis of Alzheimer's is now dominant and no longer the "prion-like hypothesis", so, it's possible that the self-propagating protein fold is not the infectious agent for prion disease either.

If it is, then it's likely that turnjng down PrP in the brain will slow or even reverse the disease. The PrP fibers probably can be degraded, if very slowly, and turning off the spigot of source material for the fold will push the equilibrium in the other direction

[0] see marc tessier levigne (current CEO of AI/biotech form Xaira)'s firing?resigning? from stanford due to fraudulent data in his lab

oigursh• 2 years ago

It's believed the UK will suffer from a batch of hidden vCJD prion disease in the next decade or so. Well needed therapy.

wlll• 2 years ago

Cite please.

masfuerte2• 2 years ago

This is very detailed:

https://www.cjd.ed.ac.uk/sites/default/files/report31.pdf

The vCJD death rate is increasing but still very low. Most of the increase is in the over seventies, which supports the theory that this is due to improved testing rather than increased illness.

I'd be more concerned about the states in the USA where it is still illegal to test for BSE.

mikeodds• 2 years ago

What’s the reasoning for making it illegal to test for BSE?

logicprog• 2 years ago

Which states are those?

nikolay5• 2 years ago

A family became scientists to find a cure and their solution is pretty simple: https://www.youtube.com/watch?v=04PmEJaYKd0

dekhn4• 2 years ago

There are no simple solutions to complex biology problems that work in a medical context.

piker• 2 years ago

…penicillin?

tim3334• 2 years ago

Scurvy? The history on that one is quite interesting https://en.wikipedia.org/wiki/Scurvy#History

atleastoptimal• 2 years ago

This will be necessary as prions have been proven to persist in the environment (plants that grow over the soil where deer with CWD decompose can transmit the disease to animals that eat them).

Prions are both 100% fatal and virtually indestructible. It's like some sort of glitch universal kill-switch biology happened upon encoded by hell itself.

j_bum• 2 years ago

Prions: the final selfish g̶e̶n̶e̶ protein

complaintdept2• 2 years ago

plants that grow over the soil where deer with CWD decompose can transmit the disease to animals that eat them

I've heard this before but the last I tried looking into it I could only find a single study with these findings. Do you know if this was ever replicated? If so, I'd be interested in reading it -- I have to wonder how careful the researchers were to isolate the raw plant material from the contaminated soil, which may have non-plant matter transmitting the prion. Plants transmitting a prion is just hard for me to believe.

A_D_E_P_T• 2 years ago

That single study came out like six months ago: https://www.sciencedirect.com/science/article/pii/S258900422...

It'll probably be a year or two until an attempt at replication is published.

Anyway, the details are all there. It's an open-access paper. (I'm enjoying this new trend where almost everything worth reading is published in open-access journals.)

beambot• 2 years ago

Prions are the ice-nine of biology...

vaylian2• 2 years ago

Sounds like you are making a reference. Can you link to an explanation?

jcul• 2 years ago

Great analogy, and one of my favorite books, of which I'm due a re-read, thanks for the reminder.

teeray• 2 years ago

Biological strangelets

Thorrez2• 2 years ago

This new treatment disables a gene that creates prions. It doesn't help you against prions from the environment.

amluto• 2 years ago

If the treatment works, it should work against acquired prions. Acquired prions are dangerous because even a minute amount that makes it to susceptible tissue (the brain) can convert endogenous prion protein to the dangerous, misfolded form.

If the treatment successfully turns off production of endogenous prion protein, then there won’t be any there to convert, and the disease (theoretically) won’t progress, and there’s some reason to believe that it might even reverse itself to at least some extent.

TeMPOraL• 2 years ago

It's like some sort of glitch universal kill-switch biology happened upon encoded by hell itself.

Proving once again, that true Eldritch horrors are not out there, but right here; not in the cosmos, but in microcosm. Nature is the ancient mad god, and it's not the telescope but the microscope that will take away your sanity.

yareally• 2 years ago

Considering some prions slowly take away your ability to sleep, it really is the stuff of nightmares

roenxi2• 2 years ago

... Prions are both 100% fatal...

I'd bet they aren't. Fatal once visible symptoms are present, probably. COVID had a CFR that was beyond horrible while the only cases that they were tracking were the ones that had made it to hospital. 100% CFR is certainly possible, but unless we have cheap ways of measuring prevalence it seems improbable. There could be common prion diseases that have managed to fly under the radar so far.

ch4s3• 2 years ago

I think the underlying biology here is pretty well known. They bump around in your body causing proteins to misfold which cascades as badly folded proteins bump into other proteins and cause misfolding. This eventually kills you, because there's no immune mechanism to purge misfolded proteins or to correct them.

flobosg3• 2 years ago

https://en.wikipedia.org/wiki/List_of_human_disease_case_fat...

unsupp0rted• 2 years ago

If this works, I wonder if we’ll discover that a bunch of diseases and conditions we thought were genetic, bacterial or viral are actually just prions causing us to go nuts.

im3w1l• 2 years ago

Amazing work. But I have some questions. The tool lowers the amount of the protein by 80%. That seems a bit low? Like I'm sure it's way better than nothing, but is it really enough?

Also they say that the gene is turned off permanently, but is that really so? I thought epigenetic changes gradually revert themselves - though I suppose that just means you have to reapply the treatment every n years.

vikramkr2• 2 years ago

Those are great questions. The answer is going to vary (quite dramatically) by the target disease, target cell type, intended effect, etc. For example they mention that 21 percent elimination can 'reduce symptoms', so you could be looking at a situation where 80% elimination slows down the progression enough that the low-symptom phase of the disease lasts long enough that you can die of some other age related complicated instead. Die with the disease instead of die because of the disease - you see that as a common goal in oncology now, and in treating diseases like HIV. Rate of reversion might depend on the cell type.

Add in the aspect that it looks like they want to work with a new AAV vector optimized for the brain (looks like the compactness of this epigenetic editor is one of the advantages which tracks, can fit in an AAV then). So if there are muliple applications required there's also questions of, what if in future applications there's an immune response against the AAV used that reduces uptake, etc etc.

These questions (along with all the others) tend to be super complicated to answer, which is why all this stuff (more mouse trials, clinical trials, manufacturing, etc) can be so long/complicated/expensive. Clinical trials are also lit in that you boil all the unknown knowns and unknowns into 'let's just check and see if it's safe and if it works.'

flobosg3• 2 years ago

Related discussion, from last week: https://news.ycombinator.com/item?id=40859876

rockinghigh• 2 years ago

The actual paper: Brainwide silencing of prion protein by AAV-mediated delivery of an engineered compact epigenetic editor https://www.science.org/doi/10.1126/science.ado7082

willmadden2• 2 years ago

Prions aren't highly communicable. You could also be struck by lightning or be hit by a car. This isn't a big priority.

VyseofArcadia• 2 years ago

It is for the researchers. They're a husband-wife team who got into the field because she carries the gene for fatal familial insomnia.

tim3334• 2 years ago

Still the tech may help with prion like diseases which are common:

There is also evidence suggesting prions may play a part in the process of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS); these have been termed prion-like diseases. (wikipedia)

vikramkr2• 2 years ago

You're saying you'd rather society not invest in fundamental research into new mechanisms of curing disease with applications to prions (medically and economically devastating), genetic disease, and potentially neurodegeneration? Also even if you were correct about this area of research not being a big priority, failing to invest in small priorities is a pretty solid way to lose your technological edge and competitiveness as a nation so let's not kneecap ourselves for no reason.

willmadden2• 2 years ago

I wrote what I meant to write. It is interesting that the first words you put in my mouth involved public funding, however.

LinuxBender2• 2 years ago

Please forgive my naive question, this is not my area of expertise. Will this be something I can inject my deer with to cure or prevent CWD, or does it require injecting something into the brain or spine? Or for that matter, how will it be administered to humans?

tim3334• 2 years ago

It's a bit hypothetical with the deer. In the article it looks like they injected the thing into the brains of mice.

LinuxBender2• 2 years ago

injected the thing into the brains of mice

That's a bit beyond my skill-set. I would probably end up with some paralyzed animals.

Gene-silencing tool shows promise as a future therapy against prion diseases

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