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What can mRNA treat next?

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Re: What can mRNA treat next?

#41

Post by Ericson2314 »

joshgev wrote: post #18
Steuard wrote: post #7

It's an indictment of something that we've had this amazing new tool for vaccine production in existence for a decade but we never even tried to use it for that until COVID because "vaccines typically don’t make much money" and "vaccines just aren’t that exciting" scientifically: "it’s nice and easy," to quote Rossi from the article. If it really does turn out that effective mRNA vaccines can be created in a straight…

I see two big problems. The science funding climate, at least in the US (I don't really know what goes on elsewhere) is in a really sad state. Projects with a low probability of success are really hard to get funded but that is precisely what you need to come up with really novel things. Curiously, science funding bodies don't seem to think of things in a probabilistic way. The second issue is the same idea, but appl…

We do fund basic research decently well, but not development. That's mostly in agreement of the above, but leads to a few differences.

In particular, if we start funding the both research & development, the public sector starts taking on all risk, so there is 0 reason to reward the private sector with IP ownership. Do a drug bounty, and then public domain the IP. I would say have the state hold the IP and license it out with cost controls, but I think having medicare actually negotiate will do that well enough.

Re: What can mRNA treat next?

#42

Post by detaro »

adeledeweylopez wrote: post #20
cjblomqvist wrote: post #12

Earlier quoted context omitted.

I agree with your sentiment, but we also need to careful with hindsight bias (i.e. it's easy to pick the winners after the fact)! It's a tricky question!

Sure, but when urgency suddenly became necessary, mRNA technology was pursued quickly, which indicates that we already knew it was promising.

A good chunk of that is that people had finally gotten a delivery mechanism to work in the past few years. The "for a decade" is misleading, because a decade ago it was an interesting idea nobody had gotten to work in a way that was useful. 2020 it was something with good promise and product development under way that could be sped up massively with more money and acceptance of it being a gamble.

Re: What can mRNA treat next?

#43

Post by jonlucc »

IAmGraydon wrote: post #22
usrusr wrote: post #19

Earlier quoted context omitted.

How would the treating of auto immune work? In my understanding you can trick the immune system into putting yet anther protein on the "kill on sight" list, by forcing the protein's mRNA blueprints into the production pipeline of some cells and... waiting, assuming that the immune system does its thing. So far so good. But isn't an autoimmune problem an entry on the "kill list" that shouldn't be there? I understand h…

https://khn.org/morning-breakout/biontech-reports-breakthrou...

I work in a pharma company, and I have been working with the animal model they use for this paper regularly for the past 4 or 5 years. I am not an mRNA therapy expert by any means, so I'll only comment on the results from the MOG35-55 and PLP EAE models.

They have good disease induction in their control groups, their targeted mRNA therapy shows pretty remarkable efficacy, and they show they can diversify a little bit with respect to the target.

These models are a little too "furry test tube" for me for this application. They work by injecting an antigen, either a short version of the myelin oligodendrocyte glycoprotein (MOG) peptide or the myelin proteolipid protein (PLP). The mouse makes antibodies against that antigen, and those antibodies also attack those antigens in their natural environments, leading to demyelination in the CNS. Well their mRNA for the MOG model makes more MOG peptide, giving the antibodies another target so they don't cause demyelination. In the human condition, there are multiple antibodies against multiple targets, so I'm not sure this is as relevant as they're suggesting, unless I'm missing something. I do want to add that this paper has a ton of work in it, and it looks pretty high quality as far as I can tell.

None of this is to say there's no value here, I'm just not sure what target they would make an mRNA for to treat human MS based on this paper or how they'd identify and test that target to get FDA approval to move into trials.

Re: What can mRNA treat next?

#44

Post by mvanaltvorst »

henron wrote: post #21
mvanaltvorst wrote: post #6

Earlier quoted context omitted.

Are there any online resources where I could learn more about what mRNA treatments could theoretically cure? Take Hashimoto's disease for example, a disease where your thyroid gland slowly gets destroyed by your immune system. If I understand correctly, mRNA could stop your thyroid gland from getting destroyed in the first place, but it cannot regenerate the thyroid gland if it has already been destroyed. Is that cor…

My mental model is that in the next decade or so mRNA treatments could be effective if a disease can be treated through the expression of a small number of proteins. These proteins could either have a direct function or stimulate an immune response. I think your example works.

What kind of proteins are important when you're looking at the immune system? Is there a protein that can attach to thyroid gland cells and signals to the body that it isn't a threat? Or is there some sort of memory of the immune system with non-threat cells, that mRNA could overwrite? I'm not a biologist, I'd love to read more about these specific inner workings without dissecting a whole undergraduate biology book.

Re: What can mRNA treat next?

#45

Post by simcop2387 »

im3w1l wrote: post #39
ProjectArcturis wrote: post #35

There are a lot of folks excited about mRNA as a "programming language" for the body. And it kind of is, but it's more complicated than that. The critical thing is that mRNA is extremely immunogenic -- that is, it provokes a strong immune response. Makes sense, since evolutionarily when we had little particles delivering RNA strands to our cells, they we viruses. So, that's great for vaccine production. Not so great…

What about hiv?

HIV is a virus, so it would seem to be a good candidate for mRNA since you'd want to make it generate an aggressive and early response to the virus. I can't even guess though what challenges would arise given that HIV likes to target the immune system itself.

Re: What can mRNA treat next?

#46

Post by Ericson2314 »

WanderPanda wrote: post #15
Steuard wrote: post #7

It's an indictment of something that we've had this amazing new tool for vaccine production in existence for a decade but we never even tried to use it for that until COVID because "vaccines typically don’t make much money" and "vaccines just aren’t that exciting" scientifically: "it’s nice and easy," to quote Rossi from the article. If it really does turn out that effective mRNA vaccines can be created in a straight…

I thought about a scheme where the years of patent protection in a particular field where there has been lack of progress is adjusted upwards, creating incentives for r&d in that particular space. The same obviously should also go into the other direction

I think patents are just a poor way to fund this stuff in general. Better to do drug bounties in which case the financing trickiness is only about who funds the human trials.

In more than medicine, there's a good argument that only monopolies can afford R&D (c.f. Bell Labs) and monopolies are also terrible, so I'm pretty down on leaving R&D to the private sector anyways. Remember we already publicly fund all the R, this just about the D.

Also, ownership, and IP ownership in general, far from being the natural order of things, is an extremely weird and hard to price financial instrument. I don't see the point of forcing it, and trying to make it work with e.g. adjustable patent lengths. That just feels like an epicycle that's very prone to regulatory capture.

Re: What can mRNA treat next?

#47

Post by thijsvandien »

Xenoamorphous wrote: post #24
dukeofdoom wrote: post #11

hair loss?

I know it’s maybe pure vanity and I definitely wish to see cancer cured first but I think the psychological impact of hair loss, especially in young people (<25), is often underestimated.

I think you can easily make that <45 in case of men, and don't forget about women.

Re: What can mRNA treat next?

#48

Post by Ericson2314 »

detaro wrote: post #42
adeledeweylopez wrote: post #20

Earlier quoted context omitted.

Sure, but when urgency suddenly became necessary, mRNA technology was pursued quickly, which indicates that we already knew it was promising.

A good chunk of that is that people had finally gotten a delivery mechanism to work in the past few years. The "for a decade" is misleading, because a decade ago it was an interesting idea nobody had gotten to work in a way that was useful. 2020 it was something with good promise and product development under way that could be sped up massively with more money and acceptance of it being a gamble.

This feels like a post-hoc rationalization to me. Of course it was less ready, and then more ready. But exactly how much of a gamble was it?

The upside is immense even considering just existing diseases, but we are really bad at pricing things that improve the status quo vs prevent bad things.

The theory, assuming a delivery mechanism is found, is rock solid---"if not when"---and I therefore wouldn't call it a gamble.

On the other hand, I don't know enough about the biology to speak to the difficulty and uncertainty around delivery mechanisms. Can we get more info on that? I suspect it wasn't too uncertain, though "oh, we change this base pair a bit and the immune system doesn't care" does seem like a relatively unplanned discovery.

Re: What can mRNA treat next?

#49

Post by rocgf »

Xenoamorphous wrote: post #24
dukeofdoom wrote: post #11

hair loss?

I know it’s maybe pure vanity and I definitely wish to see cancer cured first but I think the psychological impact of hair loss, especially in young people (<25), is often underestimated.

For better or worse, it's not the importance of a disease per se that drives innovation, it's money. So assuming that hair loss is the kind of problem that would get people to spend money, then we might see some progress here.
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