What can mRNA treat next?

Thanks for the TLDR. Based on this I'll not read it.

Thank you for the summary. We know we're deep in the weeds when heart disease and cancer are the afterthoughts among candidate diseases to treat.

I think another key takeaway is that mRNA didn't really seem to interest anyone until the pandemic came along.

Plus a flu vaccine:

> mRNA vaccines [...] generate a much stronger immune response than responses that are generated to the protein in a normal flu vaccine [...]

> One limitation of the current flu vaccines is that they take about six months to develop, meaning scientists must choose which strains they think will be prevalent in the next flu season — even before the current one is over. So by the time the vaccines are ready for distribution, a different strain may have emerged as the better target.

> An mRNA flu vaccine, on the other hand, can be developed in about a month or so, giving researchers much more time to determine which strains to protect against.

https://www.washingtonpost.com/health/2021/04/11/mrna-flu-sh...

The flu vaccine seems to me to have a better chance of working than an HIV vaccine because we have been trying for decades to come up with one for HIV, without any success at all. I'm not saying that their attempts won't work either, but it's more of a bet than a flu vaccine. An iterative improvement on the existing flu vaccines would still be very helpful.

BioNTech as well: https://biontech.de/science/pipeline

brings an odd question, will we have to have artifical exposure to diseases just to ensure our immune system is capable ?

I agree. It's easy to overstate things, but over the next several decades I could easily see a computational personalized approach to fighting cancer: read the unique immunosuppressive markers, sort out what's tractable and what's not, then deliver a mRNA payload for that particular cancer for that particular person.

For the incredibly small amount that I know, it looks like a game changer. (Like everything else, though, there's a long road from theory to practice. Implementation is going be very tough)

I was thinking about this very subject this morning, and I realised the mRNA stuff actually isn’t the exciting part.

It’s the packaging in lipid particles that is much more interesting. We can get away with this approach for vaccines because we (largely) don’t care where we deliver the payload to, just as long as we get mRNA to a cell where it can make the protein. Not sure about current formulation, but I read most LNPs end up in the liver from circulation.

The next level of tech is targeting the particles, and then it gets as tricky as other contemporary techs, because you want your targeting mechanism on the prticles to be something resembling a receptor ligand (protein/carbohydrate).

Manufacturing of those (and putting them on a lipid particle) is still a slog. If we figure out nice ways to do that (without reasonable purity) then it doesn’t matter what is in the LNP (e.g put gold particles inside cancer targeting particles and zap your cancer cells dead).

Possibly naive question: if you can differentially target any particular thing to cancer cells specifically, why not just deliver poison to kill the cells directly? I.e. chemotherapy but without any of the nasty side effects.

I thought they solved that by replacing U by 1-methyl-3'-pseudouridylyl in mRNA vaccines? I can imagine it's not great for vaccines either, you want the immune system attack the spike the mRNA codes for, not destroy the mRNA before it can do it's thing.

https://berthub.eu/articles/posts/reverse-engineering-source...

> We (probably) can't just program it to produce that protein, because it would also train the immune system to target that protein.

I am not a scientist but my understanding is that the immune system targets only what it is trained against. It doesn't target anything which is non-self without being trained beforehand.

IMO if it was otherwise there would be no need for vaccine.

So I think that it is quite feasible to make a cell to produce a new protein, for example Zolgensma [0] works that way: It creates a new gene (hence a new protein) to replace a deficient one.

[0] https://en.wikipedia.org/wiki/Onasemnogene_abeparvovec

> mRNA as a "programming language" for the body

Kinda. Programming but more like a browser JS.

You're not changing anything (your DNA) and whatever you're making is temporary and limited (especially because you can't have anything too complex or long as mRNA without that breaking up).

I think this is not just because of viruses, but also healthy autoimmunity. Finding even your own cell internals in the bloodstream would mean there is work to do for the immune system. E.g. auto-antibodies may increase with tumor burden, as cell rupture caused by apoptosis, or necrosis attract immune cells and cascade recruitment of more, which is usually a good thing.

Anyway, AFAIK the mRNA breakthrough wasn't with the mRNA itself, but rather the delivery vehicle to avoid said immune response. I don't think your example of cystic fibrosis, and generally chronic illnesses, are prime targets for mRNA based therapy, as the genetic defect isn't causally targeted by mRNA tech. You would force all cells (with non-discriminatory vehicles) to produce the missing protein repeatedly. Much better target for gene therapy.

I don't think people see the future of mRNA in substituting into the delicate machinery of the cell continuously. I think the possible therapy target are of the type raw, simple one-hit wonders. Very much alike traditional medication approaches, with the twist of excellent drug delivery avoiding extracellular pharmacokinetics, e.g. vitamin C has very different, even antagonistic roles in the intra- vs extracellular space, and of course liver-fistpass and immunological clearance. mRNA tech is not gene therapy (although, there is of course effective overlap).

I haven't read anything related to treating autoimmune diseases with mRNA, that would be quite exciting. Do you happen to have a reference for this?

I have Ulcerative Colitis, which is a form of an autoimmune disease. A vaccine as a cure would be a game changer.

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 how we can append to that list (through a fascinatingly elaborate stack of indirections), but how can we revoke an entry?

Not questioning, just willing to learn.

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 correct?

If that's possible, curing type 1 diabetes would be on the horizon as well. There's some evidence that people with t1d have latent beta cells that could be reactivated to restore normal(ish?) insulin response. That would be incredible.

Or focus on lowering costs. We learned in the pandemic how fundamentally broken the FDA is. There is no reason that things can't be faster that "operation warp speed" all the time.

Or re-focus the monetary models around either markets or patient outcomes. Right now, medicine is not a market, it's a strange game. The most money that can be made is finding a treatment that may provide a modest increased benefit over what is live, then sell it to medicare at "name your own price". This incentives high probability wins (which are typically things we already understand well).

We did not have this tool for a decade, it was still very much scientific work in progress, with a lot of practical problems to be solved. Those problems were only ironed out in 2017-2018.

You can absolutely kill or at least maim a new medical technology if you push it on the market too far and a wave of serious side effects hits you. As an example: death of Jesse Gelsinger [0] delayed genetic therapies by several years, possibly a decade or more. Scientists were afraid to touch the tools that killed a young man and produced a public backlash.

[0] https://en.wikipedia.org/wiki/Jesse_Gelsinger

This is not new at all. They tried to use mRNA vaccines for other diseases as well, but were never approved. This still holds true to this date.

edit: An example would be Dengvaxia.

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 applied to industry. There is an activation energy that you need to surpass in order to make any business profitable. If we are talking about building a business around a brand new and unproven (in a business sense) technology like mRNA, the barrier is _huge_. You need entities with very deep pockets to accept year after year of losses before you can start getting a viable business producing cutting-edge products.

In both cases I think intelligent use of government funds could be a big help. I am not big on socialism, but I have long held that this is one of the most important things a government can and should provide: subsidies for risky research and business endeavors, not to mention large-scale infrastructure projects.

Once drugs go off-patent, the subscription model is a lot less appealing. Even before then, allowing vaccines to sell for $200 per dose (I'm just making up this number) would encourage vaccine production. But you're right that this is an example of markets not doing the right thing, so it might take government, or even insurance company subsidies on vaccine development.

Permanently? I thought the standard of performance has become “reducing symptoms, maybe, we think, we’re not really sure. This is probably safe though”