Crucially, this approach doesn't require a new LNP, it works with FDA-approved formulations. We hope that this approach will enable targeted mRNA therapeutics for diverse diseases. Work led by Bettina Dietmair, James Humphries and Chris Howard. @basemrna.bsky.social

The technology is programmable and works with other targeting arms including anti-PSMA (highly expressed on prostate cancer cells) bispecifics. 6/

Bispecifics can be used by combining with the mRNA-LNP (pre-mixing) or the bispecific can be administered first (pre-targeting). 5/

As proof of concept we used anti-EGFR bispecifics to deliver mRNA to mouse breast cancer xenografts. The mRNA-payload (luciferase) is very efficiently delivered in vivo. 4/

To overcome this obstacle we developed bispecific antibodies that bind to PEG on the surface of LNPs and to cell-surface markers. 3/

Getting a high dose of mRNA to target tissues is one of the toughest problems for broad use of mRNA-LNP therapies. When administered systemically mRNA-LNPs go the liver with little delivery to other tissues. 2/

Happy to sure our protocol if helpful, just send me a DM

We use q5 which has a very low error rate. We've done a lot of ONTseq of plasmid and pcr templates and don't see any increase in error rate, but we see way better polyA integrity.

How much mRNA are you producing? We routinely use PCR to generate templates for up to 1-20mg productions. I know people that have done larger batches too.

There are some tweaks like segmented polyA tails that somewhat reduce deletions, but they're still very frequent. Worse, they are sometimes subclonal so sanger sequencing doesn't even detect the deletion. The field definitely needs better synthetic biology solutions.
doi.org/10.1261/rna....

Could be real though, polyA deletions in plasmids are really common and one of the reasons we switched to PCR-based templates.

@helengunter-mrna.bsky.social is the expert at this.

You might be a bit overqualified Scott ;)