RNAV8 Bio Joins ARPA-H Team to Pioneer Programmable RNA Medicines

RNAV8 Bio (pronounced Renovate Bio) has been selected to receive funding from the Advanced Research Projects Agency for Health (ARPA-H) for PROPEL (Programmable RNA for Optimal Precision in Therapeutic Efficacy and Localization).

RNAV8, a biofirm applying AI-driven design and laboratory validation to engineer more predictable mRNA medicines, will be part of a team led by the Rouskin Lab at Harvard Medical School with the Weissman Lab at MIT/the Whitehead Institute. The award, a one-year ARPA-H pilot of up to $4.4 million, will fund a program to turn RNA’s natural folding behavior into a precise, drug-tunable control layer for a new generation of RNA medicines. PROPEL is led by ARPA-H program manager Shannon Greene, PhD.

“The promise of mRNA has always been that it’s programmable, but in practice the relationship between a RNA’s sequence and chemistry and what it actually does has been hard to predict,” said Devan Shah, founder and CEO of RNAV8 Bio. “Our work with the Rouskin and Weissman labs is aimed squarely at that gap: learning the rules that connect sequence to function, and building them into logic-gated constructs that express where and when they should.

“Just as important, every element we discover stays answerable in the format a medicine actually ships in. We’re proud to help carry this science from a regulatory element toward a real therapeutic.”

Within PROPEL, RNAV8 Bio focuses on the therapeutic format itself. It screens protein output from pools of transfected mRNA, engineers UTRs in the delivery format, and validates results at the cargo level, for example driving cell-type-selective expression of therapeutic payloads such as gene-editing enzymes or CAR constructs.

PROPEL pursues a different kind of control

Most medicines act wherever their chemistry carries them, and most genetic therapies work by permanently changing DNA. PROPEL pursues a different kind of control. An RNA molecule’s untranslated regions (UTRs) fold into structures, and those structures set how much protein the message produces. When a small molecule binds one of those folds, the structure rearranges and the output changes, turning a dose into a dial on protein expression, without altering the genome. Bacteria use this logic openly, in elements called riboswitches; in human cells it remains largely uncharted.

“For decades we’ve read RNA sequence as a set of instructions for making a protein. What we can now read, at the scale of thousands of sequences at once, is how that sequence folds, and how a small molecule can change the fold and, with it, the output,” said Silvi Rouskin, PhD, assistant professor of microbiology, Harvard Medical School. “Human cells almost certainly already use this kind of structural control; we’ve simply never had the tools to find it systematically. PROPEL is our attempt to map it and put it to work.”

Engineering installs regulatory elements into therapeutic mRNA so that a single construct is selective by cell type through its sequence and tunable through its structure. Both rely on high-throughput mapping of how a RNA’s folds shift when a ligand binds, which flags the elements that regulate protein output before the team tests which ones a small molecule can move.

The Weissman Lab contributes massively parallel screens of human untranslated-region elements across cell types, measuring which ones set expression where.

“The untranslated regions flanking a message are among the most powerful and least exploited levers on how much protein a cell makes,” said Jonathan Weissman, PhD, professor of biology, MIT and member, Whitehead Institute. “By screening these elements across cell types, we can begin to tell which ones set expression where, turning a vague notion of ‘regulation’ into a defined, reusable parts list. That is what makes a control layer generalizable rather than a one-off trick.”

By the end of its initial phase, the collaboration aims to produce resources that do not exist today: a map of how thousands of human RNA sequences respond to small molecules, with structural models; a ranked catalogue of human UTR elements that set translation cell type by cell type; engineered UTRs that reach meaningful selectivity in a therapeutic format; and RNA sequences, natural or engineered, shown to switch structure inside human cells. Together these are meant to form a generalizable, disease-agnostic foundation for RNA medicine, according to the scientific team.

PROPEL is a program supported by ARPA-H that develops a programmable, drug-tunable control layer for RNA medicines.

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