5 ms·

Molecule restores cognition and memory in Alzheimer's disease mouse study

84 points by geox 2y ago

nick__m 2y ago
Figure s3 in the supplemental materials¹ is quite beautiful and the molecule (table s1) look simple for something that restore cognition. Lets hope that it also works in human. 1- https://www.pnas.org/action/downloadSupplement?doi=10.1073%2Fpnas.2400420121&file=pnas.2400420121.sapp.pdf https://www.pnas.org/action/downloadSupplement?doi=10.1073%2...
noleary 2y ago
> The molecule, DDL-920, works differently from recent FDA-approved drugs for Alzheimer’s disease such as lecanemab and aducanumab, which remove harmful plaque that accumulates in the brains of Alzheimer’s disease patients. While removing this plaque has been shown to slow the rate of cognitive decline, it does not restore the memory or remedy cognitive impairments. Thankful researchers are exploring some new approaches now. The amyloid hypothesis was fine, but its dominance seems to have set Alzheimer's research back by years.
- PaulKeeble 2y ago
  There was always a lot of evidence to suggest that Amyloid plaque was not the cause of the problem but a sign of the activity causing the issue and the fact it was the only pursued strategy for years speaks to a problem in medicine and research funding getting very railroaded at times. Many diseases have many potential causes but once a favourite gets selected there is a real tendency for all efforts to go towards that theory and even when early signs are its wrong it continues for years. Alzheimer research went seriously wrong for multiple decades.
  - feoren 2y ago
    In the particular case of Alzheimer's, some of the foundational studies supporting the amyloid plaque hypothesis were literally fraudulent. Railroading is a problem in general, but won't combat just straight-up fraud. Better fraud detection is needed in cases like these, but of course it's an arms race.
- m3kw9 2y ago
  [flagged]
amluto 2y ago
This appears to be a duplicate of https://news.ycombinator.com/item?id=41194750 https://news.ycombinator.com/item?id=41194750
PaulKeeble 2y ago
Whether this is valid in humans likely depends on the Alzeimers mouse model. Some of the mouse models are really good because we can inject the mouse with something humans get and they suffer a similar fate. But for a lot of these complex diseases the analogues can be very unrepresentative or require genetically modified mice and they tend to translate less well. "researchers used mice that were genetically modified to have symptoms of Alzheimer’s disease" is what I am concerned about. I remain hopeful it translates across and IDO1 has been implicated in a bunch of conditions so such a drug might find some other uses.
NeuroCoder 2y ago
I'd be curious about what the authors thoughts are on this molecule decreasing the threshold for seizures. I know they reported there were no clearly adverse effects throughout the study, but it's not like they had the mice on continuous EEG for epileptic events.
- terribleperson 2y ago
  There are drugs in use today that lower seizure threshold, e.g. some antidepressants. So I guess it's be a question of how much it decreases the seizure threshold and whether it's a worthwhile tradeoff. When the alternative is an unstoppable decline ending in death, I think pretty severe side-effects could be considered acceptable.
  - NeuroCoder 2y ago
    I know there are some extreme cases reported where antidepressants were associated with seizures, but from what I understand that's extraordinarily rare. I don't just mean it's rare in clinical trials and research. None of the physicians I've worked with have seen changes in seizure activity following years of SSRI use. The research in that area has also seemed to have petered out without an obvious mechanism or associated population to further explore. The closest thing I can think of is high dose stimulants causing tonic clinic seizures, but I'd be curious if the unintentional hyperactivity of neurons in stimulants is physiologically similar to increasing oscillatory activity. I'm not an expert in antiepileptics though so it'd be nice to get some more perspectives here
deleted 2y ago
[deleted]
robwwilliams 2y ago
This link and promotional piece from UCLA was discuss two weeks ago. At least UCLA understands PR. https://www.uclahealth.org/news/release/molecule-restores-cognition-memory-alzheimers-disease-model https://www.uclahealth.org/news/release/molecule-restores-co...
- ChrisArchitect 2y ago
  [dupe] Discussion: https://news.ycombinator.com/item?id=41194750 https://news.ycombinator.com/item?id=41194750
jmward01 2y ago
Soon mice will live forever, with 100% cognitive function, no hair loss and free of cancer. Now if only we could do the same for people.
- m3kw9 2y ago
  And then one escapes
  - jareklupinski 2y ago
    this summer, one mouse is ready to take on the world
    - justinclift 2y ago
      Is it pink, or more the brainy type? :)
- _qua 2y ago
  It would be interesting to run an experiment to see how long we could keep a mouse alive using the results of all these mouse-positive trials, treating each disease as it crops up.
- elromulous 2y ago
  That's the thing. Many of these work in mice because mice have such a short lifespan. Whereas if they lived much longer, they'd die from the side effects.
- akira2501 2y ago
  You don't go out and find mice with Alzheimer's. You develop a process to _give it to them_. Otherwise your data is useless.
- unshavedyak 2y ago
  Now I’m imagining a permanent anti aging solution found for mice, the mice get released and spread their aging immune DNA to other mice. Now we have a world being overrun by billions of mice. Neat
narrator 2y ago
With negative GABA receptor allosteric modulators there's the potential for excitotoxicity. GABA receptors are there to counteract excessive excitatory activity after all. Likely there's a small therapeutic dosage window.
shcheklein 2y ago
A bit unrelated / meta question. Since it's developed in UCLA - do they have resources to do the next phases of trials (humans, etc)? I wonder if in such cases pharma (those who obviously have enough money) care about these molecules at all? Since they probably can't put a patent on it and heavily monetize it later. Are there examples of drugs that were developed like this successfully?
- fasa99 2y ago
  It's very much patentable and thus represents an IP asset that can be traded, contracted, exchanged, etc, similar to a "technology invention". UCLA likely owns it or a part of it, so can trade it freely. This is quite very very early for a drug, so there's huge risk it will fail in human trails, so that high risk lowers the value significantly versus a phase III passed drug. There's a kazillion drugs like this, XYZ-123 type format, most of which failed or never reached Phase I, Phase II, phase III, phase IV, or phase kappa trials
- vineyardmike 2y ago
  Most labs in universities have wildly different finances. Each lab basically has to compete for funds independently of their parent university - few are funded by the school. It’s very unlikely that a lab equipped to study mice is also equipped for human studies. Those require a lot more money and different expertise and in addition to different equipment and facilities.

84 points by geox 2y ago

Figure s3 in the supplemental materials¹ is quite beautiful and the molecule (table s1) look simple for something that restore cognition. Lets hope that it also works in human. 1- https://www.pnas.org/action/downloadSupplement?doi=10.1073%2Fpnas.2400420121&file=pnas.2400420121.sapp.pdf https://www.pnas.org/action/downloadSupplement?doi=10.1073%2...

noleary 2y ago

> The molecule, DDL-920, works differently from recent FDA-approved drugs for Alzheimer’s disease such as lecanemab and aducanumab, which remove harmful plaque that accumulates in the brains of Alzheimer’s disease patients. While removing this plaque has been shown to slow the rate of cognitive decline, it does not restore the memory or remedy cognitive impairments. Thankful researchers are exploring some new approaches now. The amyloid hypothesis was fine, but its dominance seems to have set Alzheimer's research back by years.

PaulKeeble 2y ago
There was always a lot of evidence to suggest that Amyloid plaque was not the cause of the problem but a sign of the activity causing the issue and the fact it was the only pursued strategy for years speaks to a problem in medicine and research funding getting very railroaded at times. Many diseases have many potential causes but once a favourite gets selected there is a real tendency for all efforts to go towards that theory and even when early signs are its wrong it continues for years. Alzheimer research went seriously wrong for multiple decades.
- feoren 2y ago
  In the particular case of Alzheimer's, some of the foundational studies supporting the amyloid plaque hypothesis were literally fraudulent. Railroading is a problem in general, but won't combat just straight-up fraud. Better fraud detection is needed in cases like these, but of course it's an arms race.
m3kw9 2y ago
[flagged]

amluto 2y ago

This appears to be a duplicate of https://news.ycombinator.com/item?id=41194750 https://news.ycombinator.com/item?id=41194750

PaulKeeble 2y ago

Whether this is valid in humans likely depends on the Alzeimers mouse model. Some of the mouse models are really good because we can inject the mouse with something humans get and they suffer a similar fate. But for a lot of these complex diseases the analogues can be very unrepresentative or require genetically modified mice and they tend to translate less well. "researchers used mice that were genetically modified to have symptoms of Alzheimer’s disease" is what I am concerned about. I remain hopeful it translates across and IDO1 has been implicated in a bunch of conditions so such a drug might find some other uses.

NeuroCoder 2y ago

I'd be curious about what the authors thoughts are on this molecule decreasing the threshold for seizures. I know they reported there were no clearly adverse effects throughout the study, but it's not like they had the mice on continuous EEG for epileptic events.

terribleperson 2y ago
There are drugs in use today that lower seizure threshold, e.g. some antidepressants. So I guess it's be a question of how much it decreases the seizure threshold and whether it's a worthwhile tradeoff. When the alternative is an unstoppable decline ending in death, I think pretty severe side-effects could be considered acceptable.
- NeuroCoder 2y ago
  I know there are some extreme cases reported where antidepressants were associated with seizures, but from what I understand that's extraordinarily rare. I don't just mean it's rare in clinical trials and research. None of the physicians I've worked with have seen changes in seizure activity following years of SSRI use. The research in that area has also seemed to have petered out without an obvious mechanism or associated population to further explore. The closest thing I can think of is high dose stimulants causing tonic clinic seizures, but I'd be curious if the unintentional hyperactivity of neurons in stimulants is physiologically similar to increasing oscillatory activity. I'm not an expert in antiepileptics though so it'd be nice to get some more perspectives here

deleted 2y ago

[deleted]

robwwilliams 2y ago

This link and promotional piece from UCLA was discuss two weeks ago. At least UCLA understands PR. https://www.uclahealth.org/news/release/molecule-restores-cognition-memory-alzheimers-disease-model https://www.uclahealth.org/news/release/molecule-restores-co...

ChrisArchitect 2y ago
[dupe] Discussion: https://news.ycombinator.com/item?id=41194750 https://news.ycombinator.com/item?id=41194750

jmward01 2y ago

Soon mice will live forever, with 100% cognitive function, no hair loss and free of cancer. Now if only we could do the same for people.

m3kw9 2y ago
And then one escapes
- jareklupinski 2y ago
  this summer, one mouse is ready to take on the world
  - justinclift 2y ago
    Is it pink, or more the brainy type? :)
_qua 2y ago
It would be interesting to run an experiment to see how long we could keep a mouse alive using the results of all these mouse-positive trials, treating each disease as it crops up.
elromulous 2y ago
That's the thing. Many of these work in mice because mice have such a short lifespan. Whereas if they lived much longer, they'd die from the side effects.
akira2501 2y ago
You don't go out and find mice with Alzheimer's. You develop a process to _give it to them_. Otherwise your data is useless.
unshavedyak 2y ago
Now I’m imagining a permanent anti aging solution found for mice, the mice get released and spread their aging immune DNA to other mice. Now we have a world being overrun by billions of mice. Neat

narrator 2y ago

With negative GABA receptor allosteric modulators there's the potential for excitotoxicity. GABA receptors are there to counteract excessive excitatory activity after all. Likely there's a small therapeutic dosage window.

shcheklein 2y ago

A bit unrelated / meta question. Since it's developed in UCLA - do they have resources to do the next phases of trials (humans, etc)? I wonder if in such cases pharma (those who obviously have enough money) care about these molecules at all? Since they probably can't put a patent on it and heavily monetize it later. Are there examples of drugs that were developed like this successfully?

fasa99 2y ago
It's very much patentable and thus represents an IP asset that can be traded, contracted, exchanged, etc, similar to a "technology invention". UCLA likely owns it or a part of it, so can trade it freely. This is quite very very early for a drug, so there's huge risk it will fail in human trails, so that high risk lowers the value significantly versus a phase III passed drug. There's a kazillion drugs like this, XYZ-123 type format, most of which failed or never reached Phase I, Phase II, phase III, phase IV, or phase kappa trials
vineyardmike 2y ago
Most labs in universities have wildly different finances. Each lab basically has to compete for funds independently of their parent university - few are funded by the school. It’s very unlikely that a lab equipped to study mice is also equipped for human studies. Those require a lot more money and different expertise and in addition to different equipment and facilities.