We are also excited to tap into the decades of exciting chemistry for modifying and enhancing small RNA activity. @rflusi.bsky.social is one of the few people who can do the complex chemistry and build the necessary bioinformatics tools! @stanford-chemh.bsky.social @stanfordchemistry.bsky.social
Overall ALTER may enable unique insights into AGO biology and inspire translational efforts to perform non-downregulatory RNA manipulations for difficult-to-drug disorders. We showed that ALTER can be packaged into both VLPs and AAVs, hopefully allowing us to further these goals!
Retooling AGO2 as a programmable scaffold enables rapid target searching, release from targets, and enhanced interactions with native human proteins. Using MARIA (inspired by @synbiogaolab.bsky.social), we minimized potential immunogenicity concerns of our already all-human based system.
We fused human APOBEC enzymes to human AGO2 to generate ALTER, which generally exhibited higher activities and few off-target reactions than corresponding Cas13-based systems like RESCUE and CURE. We also saw that ALTER did not preferentially disrupt the native miRNA regulome!
We wondered if we could convince them to do something more. The major breakthrough was finding that small RNA guides (like siRNAs) can remodel target mRNA structure without downregulation and expose small loops accessible for other effectors to manipulate.
Small RNA programmable technologies like Cas enzymes have led to major revolutions in biology and medicine, but few have been optimized over millions of years to operate in human cells. AGO proteins are famously hijacked by miRNAs and siRNAs, but usually downregulate targets.
Excited to share our latest preprint on work led by postdoc Robert Lusi (@rflusi.bsky.social)! Introducing ALTER (AGO-Led Targeted Editing of RNA) for non-downregulatory RNA manipulation by repurposing hAGO2, non-immunogenic and capitalizing on evolution. www.biorxiv.org/content/10.6...
Really cool approach to an impactful problem from @greenahn.bsky.social @uwproteindesign.bsky.social!
Congrats Bryan, this looks super powerful!
Attend the 2025 Bringing Chemistry to Medicine Symposium to learn from leading experts in transcription, chromatin regulation, computational biology and chemical biology. Registration is free and available both in-person and virtually.
Incredibly proud of @christineisadora.bsky.social for defending her PhD work today! The first PhD from the Banik lab, and an amazing story on targeted protein relocalization and TRAMs! Her PhD work spans small molecules, neurobiology, cell engineering, and computational method development.
If you want to understand how cells function, you have to work out what proteins interact with — and where
https://go.nature.com/4hYLaol
Congrats Brian, amazing stories!
Check it out, powerful new method for optical imaging of the live ECM, from @hhmijanelia.bsky.social Group Leader Kayvon Pedram #proudofalumni #glycotime
www.nature.com/articles/s41...
Congratulations to @alesalerno.bsky.social from University of Dundee CeTPD and Christine Ng from @stanford-chemh.bsky.social who have been selected as recipients of our conference travel scholarships to attend the Proximity-based Therapeutics Keystone conference @keystonesymposia.bsky.social!
Amazing to see the LYTAC technology get to this point, catalytic extracellular degraders could open many new therapeutic opportunities or perhaps even become standard of care compared to antagonistic antibodies alone. Congrats to Lycia Tx!
