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What mRNA is good for, and what it maybe isn’t

blogs.sciencemag.org

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Re: What mRNA is good for, and what it maybe isn’t

#51

Post by FPGAhacker »

zabzonk wrote: post #20
klevertree wrote: post #5

I wrote a long essay about the same topic and came to similar conclusions as Derek Lowe: https://trevorklee.com/are-mrna-therapies-the-future-of-phar... One thing that I'd like to emphasize is how unbelievably tiny mRNA therapeutics have to be. It's probably around 30 mg, and it's hard to do it more than once every few weeks, at least judging by siRNA therapeutics (which have similar immune issues). 30 mg is really t…

> 30 mg is really tiny Not really. For example the amount of beta blocker I take for my heart problems is 5mg per day - the pill size goes down to 2.5mg.

Pretty sure they meant micrograms, not milligrams.

Re: What mRNA is good for, and what it maybe isn’t

#53

Post by TchoBeer »

landryraccoon wrote: post #36
klevertree wrote: post #5

I wrote a long essay about the same topic and came to similar conclusions as Derek Lowe: https://trevorklee.com/are-mrna-therapies-the-future-of-phar... One thing that I'd like to emphasize is how unbelievably tiny mRNA therapeutics have to be. It's probably around 30 mg, and it's hard to do it more than once every few weeks, at least judging by siRNA therapeutics (which have similar immune issues). 30 mg is really t…

> 30 mg is really tiny. It's hard to come up with a meaningful therapeutic in such a small amount of material. I'm going to echo others and ask what you mean here. A lot of drugs have effective doses lower than 30mg. Are you saying that 30mg is an unusually small dose for a pharmaceutical? Because I don't think that's true.

micrograms

Re: What mRNA is good for, and what it maybe isn’t

#54

Post by krustyburger »

swlp21 wrote: post #39
GuB-42 wrote: post #34

Earlier quoted context omitted.

I think you meant 30 µg (micrograms). And it is indeed tiny. Even for LSD "the only drug measured in micrograms", a typical dose is around 100µg. Most drugs (both the legal and illegal kind) are in the tens of milligram range.

I don't think it is correct to say only one drug is measured in µg. Levothyroxine (for underactive thyroid) is typically administered in µg doses - but patient confusion with the more common mg means most medical staff will translate any mg dose a patient claims to be taking to µg automatically. It may be atypical, but it's certainly not rare for drugs to be µg doses.

I think the earlier commenter meant ‘drug’ as in street drug. But though that may have once been true, these days there are plenty of other designer drugs that come in tiny doses, many of them not as friendly as LSD.

Re: What mRNA is good for, and what it maybe isn’t

#55

Post by tiahura »

ummonk wrote: post #47
didibus wrote: post #28

> So mRNA-based techniques have a lot of power and a lot of promise. But there’s definitely a low-hanging-fruit area here, and that’s infectious disease vaccines. Beyond that the promise holds up, big-time, but the difficulties mount up as well. It’s going to be a long story with a lot of plot twists, but I’m glad we’re telling it. Just want to emphasize the conclusion, because if you stop reading before the end, you…

It's not clear that mRNA holds any actual advantage for that low-hanging-fruit relative to other approaches though (e.g. protein subunit or DNA-based vaccines).

“The mRNA vaccine seems to be highly effective, two doses of that vaccine against this variant,” Gottlieb said, referring to the Moderna and Pfizer/BioNTech vaccines. “The viral vector vaccines from J&J and AstraZeneca also appear to be effective, about 60% effective. The mRNA vaccines are about 88% effective.”

Re: What mRNA is good for, and what it maybe isn’t

#56

Post by tgb »

fastaguy88 wrote: post #40
tgb wrote: post #12

Earlier quoted context omitted.

What error correction does RNA have? Are you just referring to the third base in the codons? DNA has some but I don't know of any for RNA, and it hardly seems worth it for most organisms to have RNA error-correction: it's better to just degrade the RNA and retranscribe it.

RNA and DNA essentially use the same genetic code, which is degenerate and thus somewhat error correcting.

You mean the degeneracy in the last base of codons that I mention? I wouldn't even call that an error correcting: would you count a file type that just skipped every third byte 'error correction'? I wouldn't. This isn't a robust system and most changes to any bases will change the protein sequence. Contrast that to DNA which does have error correction, since there are two strands instead of one and also two chromosomes with nearly identical information. Both are used to repair errors, at least some of the time. I'm not aware of such a system for RNA and it's not clear where it would get the information from - though maybe the most likely system would be a 'self-destruct' where errors are detected but since repair is impossible, the RNA is just destroyed.

Re: What mRNA is good for, and what it maybe isn’t

#58

Post by DrAwdeOccarim »

klevertree wrote: post #6
amelius wrote: post #3

> So if you’re going to give patients an mRNA injection and you don’t want to set off alarm bells in the innate immune system, you’re going to have to carefully engineer your sequences at the very least. Isn't that what substituting uracil by pseudouridine solves?

No, that substitution helps, but it doesn't solve the problem. You're still introducing foreign mRNA into the body, and the body still has millions of years of evolution telling it that foreign mRNA = invader .

It solves the TLR problem, and process/purification solves the cytosolic dsRNA problem.

Re: What mRNA is good for, and what it maybe isn’t

#59

Post by DrAwdeOccarim »

readams wrote: post #11

Worth noting that even if it's good for literally only infectious disease vaccines, we're still taking about an enormous breakthrough with the potential to save hundreds of millions of lives. Imagine vaccines for malaria, HIV, Zika, and many others.

Totally! We are entering a golden age of vaccinology.

Re: What mRNA is good for, and what it maybe isn’t

#60

Post by agentgumshoe »

I'm not clear on one thing from this: early on the author states that mRNA treatments do not create a permanent immune system memory response and need repeated treatments for continued response. But then when the author switches to the 'mRNA vaccines' section he instead refers to cancer treatment, finally circling back at the end to say 'infectious disease vaccines' are the low hanging fruit. Is that still referring to mRNA? How are they getting long term immune system 'memory' from mRNA? I can't quite understand how the articles explains that among the forward looking prospects for cancer etc.
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