State-mediated mrna translation (smrt) systems to control the expression of therapeutic mrnas - hundreds of mrna-based therapeutic candidates are in preclinical and clinical-stage development

The National Institute of General Medical Sciences awarded Motive Therapeutics, Inc. $356,446 on July 1, 2026, under the Biomedical Research and Research Training program (CFDA 93.859) to develop state-mediated mRNA translation (SMRT) technology as a platform for controlling therapeutic mRNA expression.

The Phase I SBIR project runs through June 30, 2027, with work performed in Waltham, Massachusetts. Motive Therapeutics will demonstrate the ability to use SMRT technology to design inducible ADAR (IDAR) domains that respond to an array of clinically relevant intracellular proteins and validate that coupling IDARs to SMRT on and off switches produces desired effects in vitro and in vivo. The underlying technology addresses a critical limitation of mRNA therapeutics: off-target toxicity that causes most candidates to fail at the clinical stage despite advances in modified nucleotides and lipid nanoparticle encapsulation. SMRT systems integrate controls that respond to intracellular signals to regulate where, when, and how much an mRNA is translated.

Preliminary work by the co-founders at Boston University established proof of concept for ADAR domain-mediated stop codon editing, inducible ADAR domains, optimization strategies to minimize off-target activity, and demonstration of translation modulation using IDARs with on and off switches. The company will confirm the technology functions in a commercial R&D context and demonstrate its potential value as a broadly applicable platform for tissue-specific and temporally controlled mRNA therapeutics.

Incorporating modified nucleotides and encapsulating mrnas in lipid nanoparticles (lnps) partially addresses some of the limitations of the technology, but even with these advances, most mrna therapeutics fail at the clinical stage due to off-target toxicity. Motive therapeutics is developing state-mediated RNA translation (smrt) technology as a platform for designing mrna therapeutics with integrated controls that respond to signals in the intracellular environment in ways that can control where an mrna is translated, when an mrna is translated, and/or how much mrna is translated. Preliminary work by the CO-founders at boston university included the design and validation of adenosine deaminase acting on RNA (adar) domain-mediated stop codon editing, the construction and validation of inducible adar (idar) domains, the optimization of idars to minimize off-target activity, and the demonstration of using idars plus on and off switches to modulate translation. Further development focused on the design and testing of idars that are induced by proteins, small molecule drugs, and light- and protease-mediated photocleavable linkers. Finally, preliminary work examined the utility of combining multiple sensors and switches to demonstrate the potential for delivering tissue specificity while also controlling the timing and amount of translation. IT is now critical to confirm that the technology works in a commercial r & d context and to demonstrate the potential value of the technology as a broadly applicable platform. In this phase i sbir, we propose to a) demonstrate the ability to use smrt technology to design idars that respond to an array of clinically-relevant intracellular proteins, b) demonstrate that coupling idars to smrt on and off switches produces the desired effect in vitro, and c) demonstrate that the smrt technology is effective in vivo. Aim 1. Design context-specific smrt sensors and switches for use with a diverse set of clinically-relevant intracellular activators and demonstrate context-appropriate functionality in vitro. Aim 2. Demonstrate in vivo smrt-enabled control of therapeutic mrna tissue specificity. Go/no-go criteria for progression to phase II-1) a smrt system with an on switch increases payload expression by ≥ 5X in induced cells and/or the smrt system with an off switch decreases expression by ≥ 75% in induced cells and 2) the smrt system tested in vivo increases expression of the payload by ≥ 1 order of magnitude in the liver compared to the muscle site of injection after induction. Plans for phase II-motive will advance one smrt system to phase II for 1) optimization, 2) incorporation of a therapeutic payload, and 3) in vivo characterization of biodistribution and efficacy to provide robust evidence that a smrt-enhanced mrna therapeutic improves tissue-specific delivery and tunable control of a real therapeutic payload compared to the unenhanced version in a clinically relevant animal model. The other smrt systems may also be suitable for similar advancement in indication-specific direct-to-phase II sbirs.