okay so they're prolly actually hitting TLRs & not RIG-I-likes (i blame my bias there on being a coronavirologist lol) but otherwise the rest of my tweet still stands.
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Is there a simple explanation for noobs
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so a big problem w/the early days of mRNA therapeutics is that cells have innate immune sensors designed to detect viral RNA & prevent it from getting out of hand, usually this occurs via shutting down translation temporarily or in the worst case activating RNase L...
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Totally agree. quite possibly too much IFN and not enough spike expression
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IIRC curevac were also adding a protein backbone to their mRNAs to activate TLR7/8 for innate recruitment to try increase AB production ( agoniats being trialled as adjuvants) which mythed me as, like you said, Karikos work on modified nucleosides to avoid TLRs is v important.
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I'll dig the papers out when I can!
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many things, for TLR7/8 it's the mRNA not ending up in endosomes, for RIG-I-like sensors it's structural features that we're still not fully done mapping. mRNA production & decay is very tightly controlled, a random bunch of exogeneous mRNA has many potential failure modes.
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Mentioned elsewhere in the thread, but the use of the beta-S-ARCA synthetic 5'-cap analog also seems to be incredibly important. Compare filled triangles to filled circles on the graph. https://pubmed.ncbi.nlm.nih.gov/20410931/ pic.twitter.com/YtEQFHgXUo
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