[HN Gopher] Molecule restores cognition, memory in Alzheimer's d...
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Molecule restores cognition, memory in Alzheimer's disease model
mice
Author : amichail
Score : 94 points
Date : 2024-08-08 18:34 UTC (4 hours ago)
(HTM) web link (www.uclahealth.org)
(TXT) w3m dump (www.uclahealth.org)
| gilleain wrote:
| From the paper :https://pubmed.ncbi.nlm.nih.gov/39106304
|
| edit: ok apologies, after several attempts
|
| http://www.chemspider.com/Chemical-Structure.24670873.html
|
| 3-(2-Naphthylmethyl)-4-(4-piperidinyl)-1H-pyrazol-1-ol
|
| (incorrect stuff removed ...)
| A_D_E_P_T wrote:
| That's not the one.
|
| The fulltext of the paper is here:
| https://www.pnas.org/doi/10.1073/pnas.2400420121#supplementa...
|
| The structure is in the SI. You can draw it with SMILES code:
| On1cc(c(n1)Cc1ccc2c(c1)cccc2)C1CCNCC1
|
| At: https://www.antvaset.com/smiles-to-structure
| gilleain wrote:
| oops. shouldn't try 'research' on my phone. thanks.
|
| Incidentally, I'm sure it used to be possible to google
| search using InChI. Even using the InChI-Key now doesn't work
| super well it seems. I have to quote it to get this PubMed
| link:
|
| https://pubchem.ncbi.nlm.nih.gov/compound/46204539
|
| which actually gives a link to the patent : "Compositions and
| methods for treating neurodegenerative diseases"
| RobotToaster wrote:
| Would it be naive to say it looks like quite a simple (and
| ergo, cheap) molecule to synthesise?
| amluto wrote:
| It can join this one: https://pubmed.ncbi.nlm.nih.gov/26439832/
|
| The obvious major caveat is that mice are not people, and that
| mouse models of what someone thinks are Alzheimer's-like diseases
| are not people with Alzheimer's.
| newzisforsukas wrote:
| Join it how? They seem like very different studies and
| mechanisms.
| welfare wrote:
| I think they meant join in the sense of yet another study
| performed on mice with promising results without any
| indication if it will work in humans.
|
| Come back after clinical trials.
|
| Breakthroughs in Alzheimer's seems like the medical
| equivalent of breakthroughs in battery tech.
| newzisforsukas wrote:
| ... no one is calling this a breakthrough though?
|
| The paper itself and the article on it both state it is in
| mouse models of disease _within their titles_.
|
| Seems like many here bring up this point for no reason
| other than to repeat it over and over as a low-effort
| dismissal. It is exhausting to read these threads.
|
| At the moment I am writing this, there is only a single
| comment about the actual article.
| gdudeman wrote:
| I wish breakthroughs in Alzheimer's were like breakthroughs
| in battery tech. Batteries are getting dramatically cheaper
| and denser every year with a clear path for 10+ years of
| improvements.
|
| Alzheimer's treatments today maybe slow cognitive decline
| by 3 months and cost a fortune.
| amluto wrote:
| Join as a promising small molecule that seems to treat a
| disease in mice that may be related to Alzheimer's.
| engine_y wrote:
| Thanks for having 'in model mice' in the header.
|
| Unfortunately mice disease models have not been showing efficacy
| in humans.
| bawolff wrote:
| I don't think that is true in general, it more depends on the
| disease in question.
| mbStavola wrote:
| Getting ahead of the "in mice" meme replies, it is nice to see
| further developments in the search for a cure.
| ben_w wrote:
| Aye.
|
| Lost my mum to that in the middle of the pandemic. Long mental
| decline including hemispatial neglect*, but physically (mostly)
| fine right up until the last few days in the care home, when
| she forgot about drinking -- though we had to work that out
| much later and from the autopsy as nobody around her could
| reasonably have watched her 24/7 to count glasses of water not
| consumed.
|
| * such a bizarre thing to witness: her sitting at the dinner
| table, the food eaten on only one side of her plate while the
| other side was full, and her insisting the plate was empty
| until one of us rotated it 180deg.
| Bluestein wrote:
| So sorry about your loss.-
| Kuinox wrote:
| I do comment "in mice" when the title doesn't contain "in mice"
| when it should. I see it as misleading if it doesn't contain
| it.
| Bluestein wrote:
| We've downgraded even, from "in mice" to "in mice models" ...
|
| ... don't even test on real mice anymore.-
| londons_explore wrote:
| I do wonder if medicine would do better if we simply skipped the
| efficacy tests in animals (due to the very low accuracy of animal
| models of diseases not well understood) and simply did animal
| safety tests, then moved straight onto human trials.
|
| Obviously the vast majority of treatments would be ineffective -
| and this in turn should let you design multi-treatment trials,
| where say a trial of 100 patients are used to test 50 substances,
| with each person receiving simultaneously tiny doses of ~25
| candidate treatments.
|
| Then the patient outcomes are used to identify which of the 50
| likely have some effect, and a trial is done of just that
| substance.
| nonrandomstring wrote:
| It does some anomalous that some states are moving toward
| assisted dying which (I don't personally agree with for complex
| reasons), which is essentially a very humane stance, and yet
| elderly people or those who are terminally ill cannot, it
| seems, waive their "safety right" under law and consent to be
| trial subjects for experimental drugs with high risks.
| unsupp0rted wrote:
| In Canada there's assisted dying for people with mental
| illness: perfectly physically healthy people, who might even
| decide to live a fair bit longer if they felt they were
| contributing to saving lives by allowing testing.
| mtlmtlmtlmtl wrote:
| I'm not sure what you're even suggesting here. First of
| all, according to the canadian government[1], euthanasia is
| not currently permitted in cases only involving mental
| illness. It's been delayed twice already, currently until
| 2027, and may be delayed further or scrapped entirely in
| the future for all we know.
|
| Second, what would they be testing? Drugs for their
| condition? That wouldn't apply to the type of situation
| necessary for euthanasia under Canadian law[2]:
|
| >To be considered as having a grievous and irremediable
| medical condition, you must meet all of the following
| criteria. You must:
|
| 1. have a serious illness, disease or disability
|
| 2. be in an advanced state of decline that cannot be
| reversed
|
| 3. experience unbearable physical or mental suffering from
| your illness, disease, disability or state of decline that
| cannot be relieved under conditions that you consider
| acceptable
|
| If there was an experimental treatment that might actually
| help them, these criteria would not apply.
|
| If you're suggesting safety testing of drugs for other
| illnesses, that's extremely unethical and I seriously doubt
| the medical community would be willing to do it, even with
| consent. And I seriously doubt a number of people large
| enough to give meaningful results would consent in the
| first place. It's also of dubious usefulness because any
| treatment intended for disease X might have its safety
| profile and risk/benefit analysis altered by the presence
| or non-presence of X.
|
| 1: https://www.canada.ca/en/health-canada/services/health-
| servi...
|
| 2: https://www.canada.ca/en/health-canada/services/health-
| servi...
| daedrdev wrote:
| However in the Netherlands it is permitted
| y-c-o-m-b wrote:
| Isn't this what the "Right to try" laws are designed for?
| https://en.wikipedia.org/wiki/Right-to-try_law
|
| Although it does seem like many companies are still not
| allowing this. I don't know much on the topic and I'm not
| sure why (financial reasons perhaps?) they'd refuse, but I've
| always found it absurd that we can poison ourselves to death
| (literally) with all sorts of substances legally, but
| experimentation with life saving methods are restricted. I've
| seen some very strange arguments against the experimentation
| like "well they could die sooner!" - yeah, but that's up to
| the person to decide, just like all other decisions they've
| made preceding it. A patient has the right not to choose any
| treatment at all, that could definitely make the die sooner.
| Why is this where the line is drawn for some people? It seems
| arbitrary.
| nonrandomstring wrote:
| I wasn't aware of this progress. Thanks for the link. It's
| definitely an ethical hot potato. My concern would always
| be around pressure, and being sure that a choice really is
| a choice.
| mlyle wrote:
| The research teams want to get their drug approved so it
| can help many people. This means proving it is safe and
| effective.
|
| Unfortunately, using it in a non-study context risks a
| whole lot of confusion-- if the marginal, near-death case
| that wouldn't qualify for your trial dies in a weird way,
| what do you do?
|
| Not to mention that prior to approval, there are no
| economies of scale in production.
| D-Coder wrote:
| With mouse models, you are at least guaranteed to get results
| within two years. Human models can take 10, 20, 30 years.
| qwerty9001 wrote:
| You need to look up more clinical trials horror stories.
|
| Even after animal testing performed prior.
|
| I know of participants that have passed away in such trials
| (witnessed by relatives).
|
| The "slow" process is not due to over abundance of caution. Bad
| things unfortunately do happen.
| londons_explore wrote:
| Tiny doses can generally avoid this. When you eat a banana,
| there are probably over 1 million different chemicals in
| there. There are probably a few molecules that exist nowhere
| else on earth.
|
| Yet nobody is worried about the safety of a banana, because
| the concentration of the really rare chemicals is low enough
| to not matter.
| mlyle wrote:
| The efficacy of most new drugs is barely feasible to detect
| at a small trial size, of the best guess for effective
| dose, comparing against only one other option (or nothing).
|
| Trying to microdose and test many things at once is going
| to make this signal vanish to nothing.
| londons_explore wrote:
| The logical way to do it is to have doses starting really
| tiny, then doubling every ~week.
|
| Every week, patients are given a health survey, and if
| any effect is obvious in the results data (ie. patients
| given drug 43 have, on average, a 2 C increased core body
| temperature), then the dosage of that specific drug is
| either held fixed (since it is clear we have reached the
| 'has an effect' dosage), or removed entirely from the
| trial (if whatever the effect is is deemed likely to hide
| more valuable yet smaller data from other drugs)
| PicassoCTs wrote:
| But you are dying already. Vanishing to be a stumbling around
| hull, foreign to the world. If not medicated, you would be in
| constant panic of being lost in a foreign place. Fast death
| with a chance of healing seems preferable if chosen out of
| ones own free will before it errodes away?
| 42lux wrote:
| This would prolong not shorten the process...
| AuryGlenz wrote:
| If it's a big enough effect size you wouldn't need many
| people taking it, at least for something like Alzheimers. If
| it stops/reverses it in just a few people out of 10 you'd
| know to scale up.
|
| I'd take whatever the hell you'd give me even for a .00001%
| chance of it working at a 25% chance of it screwing me up
| further if I had Alzheimers as well.
| 42lux wrote:
| Stochastic effects in small samples could lead us to scale
| up treatments that only work for those specific 10 people,
| potentially wasting resources and raising false hopes for
| the broader Alzheimer's population...
| arijun wrote:
| And what of these mouse studies?
| 42lux wrote:
| Mice are excellent models for human disease due to their
| genetic similarity, with 98% of human genes having mouse
| counterparts. Their comparable reproductive and nervous
| systems, along with susceptibility to similar diseases,
| make them valuable research subjects.
|
| DNA manipulation in mice, through breeding or gene
| editing techniques like CRISPR-Cas, allows researchers to
| study specific genes and diseases. Using mice is faster
| than conducting initial studies on humans, allowing for
| rapid testing of hypotheses and treatments before moving
| to human trials. Mice also have much shorter lifespans
| and faster reproductive cycles, enabling researchers to
| study diseases and genetic effects across multiple
| generations in a fraction of the time required for human
| studies.
|
| Maybe if OP would like to sacrifice their children and
| grand children... sounds a bit insane doesn't it?
|
| Here is a nice paper for you to read
| https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3987984/
| jdoe2020 wrote:
| I work in the side of academia that feeds drug leads to pharma
| and have seen this process.
|
| The big problem aside from time is cost and scale. You might
| start with either a million compound in silico 10000 compounds
| in a high throughout enzyme screening program. You might get
| 500 hits with reasonable affinity which you put those in cell
| cultures and get 50 compounds. Then you go a small scale mouse
| study and may get 5-10 decent hits that don't have very obvious
| tox issues. Then you do a large mouse study of those for
| efficacy. You will get 1-2 compounds that may be suitable to go
| into people and there is maybe a 10% chance you get through
| phase III and onto the market. Usually there is also a step in
| monkeys before it goes into people.
|
| The main issue here is that at each of those steps the cost
| scales 10-100x so you really, really need cut cost as much as
| possible and eliminate non promising candidates. Realistically
| if a molecule doesn't work in mice sure it could work in
| humans, but you'd be better off just doing the mouse study so
| you only need to run one trial instead of 10 and use the
| savings to invest in other trials.
|
| Human trials are insanely expensive. One of my colleagues works
| at a company that pays well over $100k for a single primate for
| preclinical testing. Doing it in people is even more expensive
| with the massive costs of just organizing and insuring a trial.
| Comparatively it is very easy and cheap to inject a couple
| dozen mice with a drug and watch them for 6 months.
|
| Also mixing trial candidates is a really bad idea, CYP liver
| enzyme reactions are a real thing and are often very different
| for humans and animals. Doing it with one drug is dangerous
| enough, but mixing 25 where one may inhibit decomposition of
| another is a recipie for dead people. You'd also need a very
| very large number of people (likely thousands) to deconvolute
| the statistical noise.
| Beijinger wrote:
| "Wei et al., have studied the subunit composition of
| g-aminobutyric acid type A receptors responsible for the tonic
| inhibition of parvalbumin positive interneurons and identified a
| small molecule (DDL-920) as a potent, efficacious, and selective
| negative allosteric modulator of these receptors."
|
| A SMALL molecule? And not formula? Odd.
| dillydogg wrote:
| I the term small molecule has a specific meaning in biopharma
| and the biochemical formula is almost certainly not going to
| reveal much information. Might as well just use the convention
| of the compound ID.
|
| Related, in the supplemental data the compound's reference is
| Ref XX. Must have slipped by the reviewers.
| aftbit wrote:
| I'm not entirely sure I understand your comment, but "small
| molecule" is a drug discovery term of art, and includes things
| with relatively high molecular weights and complex formulae.
| Anything sub-1000 daltons is generally considered a "small
| molecule".
|
| https://en.wikipedia.org/wiki/Small_molecule
| Beijinger wrote:
| With a PhD in Chemistry, I understand what a "small molecule"
| is. But by looking at the link for a few seconds, I found no
| further information about the compound. I am not a big fan of
| "secret sauce". Maybe I missed it in the paper.
| harles wrote:
| I love that "in mice" is in the title (both on HN and in the
| original article). It seems like a promising result and I really
| appreciate them not over hyping it.
| RivieraKid wrote:
| Alzheon's ALZ-801 pill should be approved within a year and
| should be basically an Alzheimer cure for 15% (current phase 3
| trial) and later 2 thirds of people.
|
| I've recently learned about this and was surprised it's somewhat
| under the radar. Am I missing something?
| robwwilliams wrote:
| The fundamental problem of the great majority of so-called "in
| mice" studies is their use of exactly 1 (one) fully inbred type
| of mouse -- C57BL/6J. Would you trust N=1 clinical trials?
|
| In this particular PNAS study you have to be hard-core reader and
| rummage around in the Methods section to uncover this awkward
| detail:
|
| "Mouse strains used were C57BL/6J (Black 6, Jackson Laboratory;
| JAX stock #000664), JAX stock #003725 (Gabrd-/- mice on a
| C57BL/6J background..."
|
| No wonder translation fails so often. It is not the mice, it is
| scientists cutting corners!
|
| Some of us working with mice use many different genotypes of mice
| to ensure somewhat more robust results that have a better chance
| to generalize across mouse genomes and perhaps even human
| populations.
|
| This is not new news. Here is a classic on this topic in
| Alzheimer's research published in Neuron in 2019:
|
| https://pubmed.ncbi.nlm.nih.gov/30595332/
|
| One more point: There is a great deal of variation in expression
| of key genes/proteins mentions in this recent PNAS study, in
| particular parvalbumin and the GABA receptors.
|
| For example parvalbumin protein levels in the hippocampus of
| different strains of mice at different ages vary over a 20-fold
| range. Here are the hard data from GeneNetwork.org;
|
| https://genenetwork.org/show_trait?trait_id=61839_VFHILDKDKS...
|
| And GABA receptors also have high levels of variation in
| hippocampus and other brain regions. Here is a good paper that
| compares mouse and human GABA receptor variation.
|
| https://pubmed.ncbi.nlm.nih.gov/22506031/
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