Alltrna Engineers tRNA Oligonucleotide with Improved Potency and Activity for In Vivo Readthrough of Premature Termination Codons

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May 18, 2023, 08:00 ET

Alltrna's ML-driven platform optimizes sequence and modifications from natural tRNAs to significantly increase premature termination codon (PTC) readthrough
First Alltrna-engineered tRNA oligonucleotide shows in vivo universal readthrough of a shared genetic mutation, found in thousands of rare diseases, independent of gene and mutation location
Data demonstrate the power of Alltrna's platform to design and deliver tRNA medicines to restore disrupted protein production for patients with Stop Codon Disease, representing thousands of different diseases caused by a PTC mutation

CAMBRIDGE, Mass., May 18, 2023 /PRNewswire/ -- Alltrna, a Flagship Pioneering company unlocking transfer RNA (tRNA) biology and pioneering tRNA therapeutics to regulate the protein universe and resolve disease, today announces the presentation of the first proof-of-concept data at multiple scientific forums this month. Presentations include invited talks at the TIDES USA Oligonucleotide and Peptide Therapeutics conference and the American Society of Gene and Cell Therapy (ASGCT) 2023 Annual Meeting. The data validate that Alltrna's platform, enabled by machine learning (ML), can design, modify, produce, and deliver engineered tRNA oligonucleotides with dramatically increased potency and activity to readthrough PTC mutations and restore the production of full-length proteins, independent of gene and mutation location.

"These data confirm that we can deploy our first-in-field platform, which optimizes tRNA nucleotide sequence and modifications, to turn tRNA's sophisticated biology into programmable medicines with powerful potential therapeutic properties," said Michelle C. Werner, CEO of Alltrna. "With our unparalleled insights into tRNA biology, we are systematically designing tRNA medicines for Stop Codon Disease to unify the treatment of thousands of rare and common human diseases driven by premature termination codons. We are proud to demonstrate for the first time that such a goal may no longer be out of reach."

The proof-of-concept data demonstrate that the application of automated high-throughput sequence and ML-driven modification optimization through Alltrna's unique platform can significantly increase engineered tRNA activity. In addition, in a PTC-driven cellular oncology model, Alltrna's engineered tRNA oligonucleotide rescues tumor suppressor activity and downstream function to nearly normal levels, outperforming small molecules for PTC readthrough. Further, in patient-derived cells and an animal model of a rare human genetic disease with a PTC mutation, Alltrna's engineered tRNA oligonucleotide restores full-length protein expression. Alltrna shows its engineered tRNA oligonucleotide has universal readthrough activity for shared genetic mutations regardless of gene or location in 25 disease models, 14 different genes, and seven different mutation locations on a single gene.

"To my knowledge, this is the first time that an engineered, modified tRNA oligonucleotide has restored full-length protein production of a gene with a PTC mutation in an animal model, and as such, this is a momentous occasion in the field of tRNA biology," said Rachel Green, Ph.D., Chair of Alltrna's Scientific Advisory Board and Bloomberg Distinguished Professor in the Department of Molecular Biology and Genetics at the Johns Hopkins University School of Medicine. "The optimization of tRNA payload and targeting will unlock a whole new class of medicines to restore disrupted protein production, regardless of target, for thousands of diseases with the same underlying genetic mutation."

tRNAs not only play a central role in the translation of mRNA into proteins but also are programmable molecules with a diverse biology of sequences and modifications. There exist approximately 10³⁴ tRNA sequences with more than 120 natural and synthetic modifications possible for each nucleotide, yielding the potential to generate more engineered tRNA oligonucleotides than atoms in the universe. Alltrna's platform uniquely combines internal expertise and proprietary machine learning tools to harness the combinatorial potential of tRNA sequences and modifications that are key to structure, function, and stability.

About Stop Codon Disease

Stop Codon Disease encompasses thousands of rare and common diseases that stem from nonsense mutations, where the code for an amino acid has been mutated into a "stop" codon, also known as a premature termination codon (PTC) or nonsense mutation. This results in a truncated or shortened protein product with no or altered biological activity that causes disease. Approximately 10% of all people with a genetic disease have Stop Codon Disease, representing about 30 million people worldwide. Alltrna is engineering tRNA therapeutics that can read these PTC mutations and deliver the desired amino acid, thereby restoring the production of the full-length protein.

About Alltrna

Alltrna unlocks tRNA biology to correct disease. The company's platform incorporates AI/ML tools to learn the tRNA language and deliver diverse programmable molecules with broad therapeutic potential. Alltrna has an unprecedented opportunity to advance a single tRNA medicine to unify treatment across a wide range of diseases with the same underlying genetic mutation. Alltrna was founded in 2018 by Flagship Pioneering. For more info, visit www.alltrna.com.

About Flagship Pioneering

Flagship Pioneering conceives, creates, resources, and develops first-in-category bioplatform companies to transform human health and sustainability. Since its launch in 2000, the firm has, through its Flagship Labs unit, applied its unique hypothesis-driven innovation process to originate and foster more than 100 scientific ventures, resulting in more than $100 billion in aggregate value. To date, Flagship has deployed over $3.3 billion in capital toward the founding and growth of its pioneering companies alongside more than $20 billion of follow-on investments from other institutions. The current Flagship ecosystem comprises 43 transformative companies, including Denali Therapeutics (NASDAQ: DNLI), Evelo Biosciences (NASDAQ: EVLO), Foghorn Therapeutics (NASDAQ: FHTX), Indigo Agriculture, Moderna (NASDAQ: MRNA), Omega Therapeutics (NASDAQ: OMGA), Sana Biotechnology (NASDAQ: SANA), and Seres Therapeutics (NASDAQ: MCRB).