What can mRNA treat next?

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.

Depending on your defect, CF can either under-produce CFTR, produce deficient CFTR, or produce no CFTR. I’d imagine each of these scenarios has different viability for mRNA theraputics.

> 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

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...

What about hiv?

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).

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)

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 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.

Because the article is about him and the company he (co)founded.

Because he/his company is the subject of the article?

The headline doesn't make that all that clear, but everything about the article seems to.

You could, but keep in mind mRNA occurs in 3D and thermodynamic and kinetic forces play a huge role in biochemistry, so it’s quite a bit more complicated than your average program.