NSF Awards Grant for Evolution-inspired Design of Therapeutic RNAs

A team led by Dr. Samie Jaffrey, the Greenberg-Starr Professor of Pharmacology at Weill Cornell Medicine, has been awarded a three-year, $1.65 million grant for RNA research under a biotechnology-development program run by the U.S. National Science Foundation.

The competitive Molecular Foundations for Biotechnology program funds cutting-edge research that lays the groundwork for future clinical and industrial biotechnologies. The new award is one of nine that have been given to research teams across the United States this year, with funding assistance from the National Institutes of Health, to advance the promise of RNA-based therapeutics and other products.

Dr. Jaffrey and co-principal investigator Dr. Matthew Shoulders, a chemistry professor at the Massachusetts Institute of Technology, will use their award to develop general techniques for designing RNAs to have desired biological activities.

“We’re honored to have been chosen for this award, which we hope will enable us to accelerate progress in this challenging, but highly promising, field,” Dr. Jaffrey said.

RNA, ribonucleic acid, is a chemical cousin of DNA and is ubiquitous in cells. Messenger RNA molecules (mRNAs) are single-stranded and work as go-betweens in the conversion of genetic information to proteins. Other, RNAs, called noncoding RNAs, have a variety of regulatory functions, and form parts of important cellular machines such as protein-making ribosomes.

Because RNAs are capable of binding tightly and with high specificity to proteins as well as to other RNAs and DNA, they are viewed as having great potential as therapeutics. Yet their therapeutic use so far has been limited mostly to mRNA-based vaccines, which encode viral proteins to stimulate immune responses.

“RNAs can actually do so much more, and we’re particularly interested in their ability to bind to proteins to create new protein complexes and cellular signaling events,” Dr. Jaffrey said.

Getting RNAs to act as “molecular glue” in this sense is virtually impossible to do with direct design techniques, given the complexity of RNA biology. Scientists generally can’t predict in advance how any large strand of RNA will fold up in a particular cellular environment, and what biological activity it will have. Therefore, Dr. Jaffrey and Dr. Shoulders will develop a more indirect and iterative design approach that mimics biological evolution.

Their system is based on one that Dr. Shoulders developed for evolving therapeutic proteins, which uses a virus that is engineered to replicate as the protein exhibits improved functions. Dr. Jaffrey and Dr. Shoulders have created new viruses that replicate depending on the biological properties of a viral-encoded RNA. As the virus replicates, the RNA undergoes continuous mutations allowing improved RNAs to drive viral replication.

“This system creates a system of Darwinian evolution, where RNAs evolve powerful functions in cells,” Dr. Jaffrey said. “The long-term goal is to use such systems to discover therapeutic RNAs that we could never have even imagined when taking the traditional design approach.”

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