Combinatorial optimization of mRNA structure, stability, and translation for RNA-based therapeutics
Why is this work in the frame?
A frame that forgets how it found something cannot be audited. These are the routes that admitted this work.
No Canadian affiliation. An affiliation-only frame — the usual design — would never have seen this work. It is one of the works that make the case for inverting the frame.
Machine scores (provisional)
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
- Teacher spread
- 0.261 · how far apart the two teachers sit on this one work
- Validation status
score_only:v0-immature-baseline· verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it
Abstract
Therapeutic mRNAs and vaccines are being developed for a broad range of human diseases, including COVID-19. However, their optimization is hindered by mRNA instability and inefficient protein expression. Here, we describe design principles that overcome these barriers. We develop an RNA sequencing-based platform called PERSIST-seq to systematically delineate in-cell mRNA stability, ribosome load, as well as in-solution stability of a library of diverse mRNAs. We find that, surprisingly, in-cell stability is a greater driver of protein output than high ribosome load. We further introduce a method called In-line-seq, applied to thousands of diverse RNAs, that reveals sequence and structure-based rules for mitigating hydrolytic degradation. Our findings show that highly structured "superfolder" mRNAs can be designed to improve both stability and expression with further enhancement through pseudouridine nucleoside modification. Together, our study demonstrates simultaneous improvement of mRNA stability and protein expression and provides a computational-experimental platform for the enhancement of mRNA medicines.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
The record
- Venue
- Nature Communications
- Topic
- RNA and protein synthesis mechanisms
- Field
- Biochemistry, Genetics and Molecular Biology
- Canadian institutions
- —
- Funders
- Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNational Institute of General Medical SciencesNational Science FoundationDamon Runyon Cancer Research FoundationCanadian Institutes of Health ResearchChemistry, Engineering and Medicine for Human Health, Stanford UniversityStanford Bio-XUniversity of California, San FranciscoBaiduOregon State UniversityPfizerNational Cancer InstituteNational Institutes of Health
- Keywords
- PseudouridineTranslation (biology)Messenger RNARNARibosomeComputational biologyStability (learning theory)Cell biologyBiologyComputer scienceTransfer RNABiochemistryGene
- Has abstract in OpenAlex
- yes