Gene-silencing tool shows promise as a future therapy against prion diseases(news.mit.edu)
news.mit.edu
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
76 comments
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...
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.
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.
> 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.
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.
> 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.
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.
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.)
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.)
Here’s a study from 2015: https://www.sciencedirect.com/science/article/pii/S221112471...
Thanks, sibling to this comment posted the one I was thinking of. The study you posted appears to confirm their findings. This is...alarming.
> ... 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.
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.
Interpreting one-link comments is an excercise in creativity, but making some guesses:
1) You didn't check the source for the CFR. Wikipedia links an article that doesn't mention CFR or even use the word fatal. And as recently as '08 they were discovering that what they thought was one disease is actually 2.
2) I just wrote a comment explaining why a 100% CFR would be precise but likely not accurate. In case you thought it was, take a moment to reflect that linking to a table where the CFR is 100% isn't a refutation. That number is probably precise but likely not accurate. We don't seem to be good at detecting "mild" prion diseases.
3) Even if by some miracle that table is accurate and precise ... that is one disease. If you want to bet that prions only cause one disease then you're welcome to - but I'm still willing to bet that there are other prion diseases to be discovered that are less lethal.
1) You didn't check the source for the CFR. Wikipedia links an article that doesn't mention CFR or even use the word fatal. And as recently as '08 they were discovering that what they thought was one disease is actually 2.
2) I just wrote a comment explaining why a 100% CFR would be precise but likely not accurate. In case you thought it was, take a moment to reflect that linking to a table where the CFR is 100% isn't a refutation. That number is probably precise but likely not accurate. We don't seem to be good at detecting "mild" prion diseases.
3) Even if by some miracle that table is accurate and precise ... that is one disease. If you want to bet that prions only cause one disease then you're welcome to - but I'm still willing to bet that there are other prion diseases to be discovered that are less lethal.
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.
Yes, but there's quite a bit of variation in how susceptible an individual's PrP is (genetic variation) to a particular strain of prion. That matters a LOT in terms of likelihood of getting infected, and duration of disease progression.
This new treatment disables a gene that creates prions. It doesn't help you against prions from the environment.
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.
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.
Hmm, interesting. I wonder why the article doesn't mention that possibility.
>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
Yeah that's true, but given how ubiquitous PRNP is in mammals, this could also produce some form of memory, cognitive, or other deficit.
Yeah that's true, but given how ubiquitous PRNP is in mammals, this could also produce some form of memory, cognitive, or other deficit.
Prions: the final selfish g̶e̶n̶e̶ protein
Prions are the ice-nine of biology...
Sounds like you are making a reference. Can you link to an explanation?
Great analogy, and one of my favorite books, of which I'm due a re-read, thanks for the reminder.
Biological strangelets
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
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.
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.
> 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.
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
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
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.
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A family became scientists to find a cure and their solution is pretty simple: https://www.youtube.com/watch?v=04PmEJaYKd0
There are no simple solutions to complex biology problems that work in a medical context.
Scurvy? The history on that one is quite interesting https://en.wikipedia.org/wiki/Scurvy#History
Actually, that's a pretty good counterexample, and I guess it's fair to list a few other nutritional diseases as well (rickets, beriberi, pellagra) that have straightforward causes, and treatments with minimal side effects.
…penicillin?
using a byproduct of mold to cure a bacterial infection isn't simple.
Merely noticing it was a rare occurrence (Fleming got lucky with his dirty lab), it only works on gram positive bacteria, and importantly, use of penicillin leads to evolution of antibiotic resistance, reducing the utility of penicillin. That last point especially is a highly non-simple process.
Like just about anything in medical biology, there is a simple narrative taught to the general public, and then there's the reality as it stands in modern medical research and practice.
For prions, I'm sure people can find any number of ways to module prion activity in vitro, most of which won't work in vivo/in the real world, for messy complex reasons. To use machine learning parlance, a feature like the existence of a TED talk by the creators of a medical treatment being True highly correlates with the ineffectiveness of the treatment (same as "If published in Nature, it's almost certainly wrong!")
Merely noticing it was a rare occurrence (Fleming got lucky with his dirty lab), it only works on gram positive bacteria, and importantly, use of penicillin leads to evolution of antibiotic resistance, reducing the utility of penicillin. That last point especially is a highly non-simple process.
Like just about anything in medical biology, there is a simple narrative taught to the general public, and then there's the reality as it stands in modern medical research and practice.
For prions, I'm sure people can find any number of ways to module prion activity in vitro, most of which won't work in vivo/in the real world, for messy complex reasons. To use machine learning parlance, a feature like the existence of a TED talk by the creators of a medical treatment being True highly correlates with the ineffectiveness of the treatment (same as "If published in Nature, it's almost certainly wrong!")
Aspirin?
Aspirin causes stomach bleeding due to its anti-clotting effect due to nonselective binding and inhibition to COX-1 and COX-2; see the list of https://en.wikipedia.org/wiki/Aspirin#Adverse_effects to see all the complications that arise from this relatively innocuous drug. 43 deaths in the US in a single year (mostly people taking the drug as a poison). See details in https://en.wikipedia.org/wiki/Salicylate_poisoning showing the all the kinds of human biology aspirin interacts with that don't directly contribute to pain suppression. The main reason for fewer people dying from aspirin was a shift to other drugs.
Millions of people use aspirin everyday to relieve aches and pains. 43 deaths is nothing compared to the benefits, especially since those people are intentionally overdosing with the intention of killing themselves.
I don't think that this is GP's point. The point is rather that biology is complex and solutions to biological problems are always complex even if they are accompanied by a simple narrative.
Simple solutions can still have complex effects. There's no contradiction here.
Some of us are explicitly forbidden to take aspirin by their Dr. so the population of asprin takers is biased towards a cohort for whom asprin is safe.
A lot more people die from Tylenol, and millions accumulate damage to their livers, but it is still OTC, and people believe it's less dangerous than Aspirin.
Except that for women that are pregnant or nursing and babies under 6 months old, Tylenol _is_ less dangerous than Aspirin. (It's the only OTC painkiller or antipyretic available that's considered safe.)
Which kinda leads us back to the greater point here... There are no simple answers to complex biological problems.
Which kinda leads us back to the greater point here... There are no simple answers to complex biological problems.
Probably, but the other damage from Tylenol is that it's been misused to lower fevers that don't need to be lowered and thus disarming the immune system.
That's a huge misconception and poor science. In fact, enteric-coated aspirin is worse as it could cause bleeding in the intestines, which is worse. There are plenty of studies that show taking aspirin with vitamin C or DGL does not cause bleeding! I think taking it alongside collagen/gelatin also prevents bleeding.
There was a sublingual form, which I cannot find (Fasprin). Also, there's Vazalore, which might be liposomal. I don't know, but the effervescent Aspirin C by Bayer is amazing! It works very well for gargles for sour throat, too!
There was a sublingual form, which I cannot find (Fasprin). Also, there's Vazalore, which might be liposomal. I don't know, but the effervescent Aspirin C by Bayer is amazing! It works very well for gargles for sour throat, too!
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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.
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.
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.'
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.'
It's believed the UK will suffer from a batch of hidden vCJD prion disease in the next decade or so. Well needed therapy.
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.
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.
What’s the reasoning for making it illegal to test for BSE?
From the USDA site:
Q. Why can't we test all beef for BSE safety?
A. BSE tests are not conducted on cuts of meat, but involve taking samples from the brain of a dead animal to see if the infectious agent is present. We know that the earliest point at which current tests can accurately detect BSE is 2-to-3 months before the animal begins to show symptoms. The time between initial infection and the appearance of symptoms is about 5 years. Since most cattle that go to slaughter in the United States are both young and clinically normal, testing all slaughter cattle for BSE might offer misleading assurances of safety to the public.
Q. Why can't we test all beef for BSE safety?
A. BSE tests are not conducted on cuts of meat, but involve taking samples from the brain of a dead animal to see if the infectious agent is present. We know that the earliest point at which current tests can accurately detect BSE is 2-to-3 months before the animal begins to show symptoms. The time between initial infection and the appearance of symptoms is about 5 years. Since most cattle that go to slaughter in the United States are both young and clinically normal, testing all slaughter cattle for BSE might offer misleading assurances of safety to the public.
A positive test would damage the cattle industry.
Which states are those?
Cite please.
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?
It's a bit hypothetical with the deer. In the article it looks like they injected the thing into the brains of mice.
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.
That's a bit beyond my skill-set. I would probably end up with some paralyzed animals.
I don't think they have a treatment that works anyway. The thing in the article is just a step in that direction.
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.
Related discussion, from last week: https://news.ycombinator.com/item?id=40859876
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Prions aren't highly communicable. You could also be struck by lightning or be hit by a car. This isn't a big priority.
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.
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)
>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)
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.
I wrote what I meant to write. It is interesting that the first words you put in my mouth involved public funding, however.