[HN Gopher] Gene-silencing tool shows promise as a future therap...
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Gene-silencing tool shows promise as a future therapy against prion
diseases
Author : gmays
Score : 213 points
Date : 2024-07-11 19:21 UTC (1 days ago)
(HTM) web link (news.mit.edu)
(TXT) w3m dump (news.mit.edu)
| el_benhameen wrote:
| 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 wrote:
| 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.
| dyauspitr wrote:
| There's a decent TED talk as well by the woman involved
| (Vallabh)
| gushogg-blake wrote:
| 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_ wrote:
| 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 wrote:
| 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 wrote:
| 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 wrote:
| 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 wrote:
| Cite please.
| masfuerte wrote:
| 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 wrote:
| What's the reasoning for making it illegal to test for BSE?
| masfuerte wrote:
| A positive test would damage the cattle industry.
| tptacek wrote:
| 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.
| logicprog wrote:
| Which states are those?
| nikolay wrote:
| A family became scientists to find a cure and their solution is
| pretty simple: https://www.youtube.com/watch?v=04PmEJaYKd0
| dekhn wrote:
| There are no simple solutions to complex biology problems that
| work in a medical context.
| piker wrote:
| ...penicillin?
| dekhn wrote:
| 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!")
| nikolay wrote:
| Aspirin?
| dekhn wrote:
| 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.
| dyauspitr wrote:
| 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.
| thinkfaster wrote:
| 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.
| vaylian wrote:
| 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.
| FeepingCreature wrote:
| Simple solutions can still have complex effects. There's
| no contradiction here.
| nikolay wrote:
| 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!
| nikolay wrote:
| 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.
| nucleardog wrote:
| 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.
| nikolay wrote:
| 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.
| tim333 wrote:
| Scurvy? The history on that one is quite interesting
| https://en.wikipedia.org/wiki/Scurvy#History
| dekhn wrote:
| 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.
| atleastoptimal wrote:
| 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 wrote:
| Prions: the final selfish gene protein
| complaintdept wrote:
| > 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 wrote:
| That single study came out like six months ago: https://www.s
| ciencedirect.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.)
| flobosg wrote:
| Here's a study from 2015: https://www.sciencedirect.com/sci
| ence/article/pii/S221112471...
| complaintdept wrote:
| Thanks, sibling to this comment posted the one I was
| thinking of. The study you posted appears to confirm their
| findings. This is...alarming.
| beambot wrote:
| Prions are the ice-nine of biology...
| vaylian wrote:
| Sounds like you are making a reference. Can you link to an
| explanation?
| bell-cot wrote:
| https://en.wikipedia.org/wiki/Ice-nine
| dudeinjapan wrote:
| https://youtu.be/moSFlvxnbgk?si=oySyULUikorE8Gj_
| jcul wrote:
| Great analogy, and one of my favorite books, of which I'm due
| a re-read, thanks for the reminder.
| teeray wrote:
| Biological strangelets
| Thorrez wrote:
| This new treatment disables a gene that creates prions. It
| doesn't help you against prions from the environment.
| amluto wrote:
| 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.
| Enginerrrd wrote:
| >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.
| TeMPOraL wrote:
| > _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 wrote:
| Considering some prions slowly take away your ability to
| sleep, it really is the stuff of nightmares
| tetris11 wrote:
| (nods soberly, whilst sipping 10th coffee of the day)
| roenxi wrote:
| > ... 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 wrote:
| 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.
| Enginerrrd wrote:
| 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.
| flobosg wrote:
| https://en.wikipedia.org/wiki/List_of_human_disease_case_fat.
| ..
| unsupp0rted wrote:
| 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 wrote:
| 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.
| vikramkr wrote:
| 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.'
| flobosg wrote:
| Related discussion, from last week:
| https://news.ycombinator.com/item?id=40859876
| rockinghigh wrote:
| 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
| willmadden wrote:
| 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 wrote:
| 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.
| tim333 wrote:
| 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)
| vikramkr wrote:
| 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.
| LinuxBender wrote:
| 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?
| tim333 wrote:
| It's a bit hypothetical with the deer. In the article it looks
| like they injected the thing into the brains of mice.
| LinuxBender wrote:
| _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.
| tim333 wrote:
| I don't think they have a treatment that works anyway. The
| thing in the article is just a step in that direction.
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