Alltrna Pioneers New Processes to Synthesize Chemically Modified tRNAs

  • Oral presentation at TIDES USA 2024 demonstrates chemical synthesis, impurity identification and control, and physicochemical characterization of chemically modified tRNAs to prepare to test as a novel drug entity
  • Additional data presented at TIDES leverage newly developed homology models and PK/PD in vivo assays to optimize engineered tRNAs

CAMBRIDGE, Mass., May 16, 2024 – Alltrna, a Flagship Pioneering company unlocking transfer RNA (tRNA) biology and pioneering tRNA therapeutics to regulate the protein universe and resolve disease, today announces new data to be presented at TIDES USA 2024. An oral presentation will demonstrate Alltrna’s capabilities to synthesize chemically modified tRNA oligonucleotides with a focus on yield, purity, stability, and scaling, and a poster details the building of 3D homology models to support tRNA structure-based drug design.

“Chemically modified tRNAs have not previously been produced successfully at a scale required for preclinical development and clinical trials. The data in our oral presentation demonstrate how Alltrna has pioneered the chemical synthesis of modified tRNA oligonucleotides with a focus on yield, purity, proper folding, and stability – laying the essential foundation to scale them for therapeutic development,” said Michelle C. Werner, CEO of Alltrna.

“Today’s siRNA synthesis methods have not been able to accommodate tRNA length, which is longer than siRNA oligonucleotides, and processes to produce mRNA do not work well for synthesizing engineered tRNAs, which require coupling of chemically modified nucleotides,” said William Kiesman, Ph.D., Chief Technology Officer of Alltrna. “With years of focused research, we have defined new oligonucleotide synthesis capabilities to meet the length and purification requirements needed to synthesize chemically modified tRNAs – efficiently, reproducibly, and at-scale. We have also set the foundations for quality control and specifications and are on-track to support CGMP manufacturing of our engineered tRNAs.”

Oral Presentation: Manufacturing Strategies for Chemically Modified tRNAs

To establish manufacturing processes for the new modality of chemically modified, engineered tRNA medicines, Alltrna built proprietary analytical techniques to characterize the synthesis processes, identify impurities, and understand key synthesis parameters. Leveraging these new technologies, data show that Alltrna can drive significant improvements in yield and purity, laying the foundation for end-to-end, flexible and scalable development capabilities. Alltrna scientists are using these processes to supply the initial development pipeline and developing further processes for the synthesis, purification, and drug product unit operations to manufacture high-quality drug products at-scale.

Werner added, “The data presented on our 3D homology models demonstrate how we are continuing to extend our first-in-field platform to turn tRNA’s complex biology into powerful medicines by understanding how sequences and modifications affect tRNA structure, folding, stability, and LNP packing, which in turn affects activity.”

Poster Presentation: Building 3D Homology Models To Support tRNA Structure-Based Drug Design

To develop new modeling methods optimized for tRNA and its many chemical modifications, Alltrna generated homology models using published tRNA crystal data. Alltrna’s data show that the company can test and optimize homology models of tRNAs to match crystal structures across a series of templates. These homology models of engineered tRNAs were compared to published structures by approximating solvent accessibility and quantifying interactions and geometries, demonstrating that our predicted 3D structures maintained the key spatial arrangements and non-covalent interactions of properly folded tRNAs. The data presented validate Alltrna’s approach to computational modeling of natural and engineered tRNAs to elucidate structure and create a launch point for hypothesis generation to examine metabolic stability, lipid nanoparticle packing, and complex tRNA-partner interactions.

About Alltrna

Alltrna unlocks tRNA biology to treat disease. The company’s platform incorporates AI/ML tools to develop and deliver diverse programmable molecules with broad therapeutic potential. Alltrna has an unprecedented opportunity to advance a single tRNA medicine to readthrough premature stop codons and unify treatment across a wide range of diseases with the same underlying genetic mutations. Alltrna was founded in 2018 by Flagship Pioneering. For more info, visit

Media Contacts

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Josephine Zorbo, Ph.D., Flagship Pioneering,