Alltrna Presents Preclinical Data Demonstrating Proof-of-Concept for First tRNA Development Candidate

Data demonstrate engineered tRNA from company's first development candidate restores protein production to clinically meaningful levels in two disease models driven by the same premature termination codon

CAMBRIDGE, Mass., Dec. 9, 2024 /PRNewswire/ -- Alltrna, a Flagship Pioneering company unlocking transfer RNA (tRNA) biology and pioneering tRNA therapeutics to regulate the protein universe and resolve disease, today announced the presentation of new preclinical data, including of the company's first tRNA development candidate, AP003. AP003 is a chemically modified, engineered tRNA oligonucleotide in a clinically validated, liver-directed lipid nanoparticle (LNP) that can readthrough the arginine to TGA (Arg-TGA) premature termination codon (PTC). A single dose of AP003 tRNA showed robust in vivo restoration of protein production to clinically meaningful levels in two transgenic Stop Codon Disease mouse models, methylmalonic acidemia (MMA) and phenylketonuria (PKU). The data were presented at the Nature Conference: RNA at the Bench and Bedside IV, taking place December 9-11 at The Salk Institute in La Jolla, California.

"These data represent an important milestone for Alltrna, demonstrating robust in vivo activity and clinically relevant protein restoration across two disease models representing two different inborn errors of metabolism driven by the same premature termination codon," said Michelle C. Werner, CEO of Alltrna and CEO-Partner at Flagship Pioneering. "We believe these data support the potential for a basket approach to developing AP003 for the treatment of many rare genetic liver diseases caused by an Arg-TGA PTC, including the organic acidemias and aminoacidopathies represented by our MMA and PKU Stop Codon Disease mouse models. We look forward to advancing our IND-enabling studies for AP003."

In an MMA Stop Codon Disease mouse model, developed by Alltrna and collaborators, a single dose of the tRNA component of AP003 (tRNA-3) in a LNP delivery system restored in vivo protein levels of methylmalonyl-CoA mutase (MMUT) to approximately 25% of wildtype levels at Day 4, well above the 1-2% protein rescue considered to be clinically meaningful in MMA by key opinion leaders. Protein levels remained above 1-2% of wildtype 14 days after dosing, which was the longest time point tested.

In a new Stop Codon Disease mouse model of PKU, developed by Alltrna, a single dose of AP003 demonstrated phenylalanine hydroxylase (PAH) restoration to 7% of wildtype levels within 72 hours, exceeding the clinically relevant 3% protein rescue target defined by key opinion leaders. Further, this PAH protein restoration resulted in a meaningful 76% reduction of phenylalanine (Phe) levels from baseline, as PAH is the enzyme responsible for breaking down Phe. When PAH is mutated or deficient, Phe accumulates to toxic levels, causing the hallmark elevated Phe levels observed in PKU.

"Based on tRNA's critical role in protein translation, a single tRNA medicine is uniquely positioned to address multiple diseases that have a shared mutation. We are excited to see that our engineered tRNA can in fact achieve significant restoration of protein production above clinically relevant target levels in both MMA and PKU, where a premature termination codon would otherwise create a truncated or missing protein," said Chris Henderson, Ph.D., Chief Scientific Officer of Alltrna. "In addition, to our knowledge, these are the first preclinical data with a tRNA candidate demonstrating that protein restoration leads to meaningful changes in levels of a clinical biomarker (Phe) that is recognized as a registrational endpoint in humans."

Dr. Henderson continued, "We are delighted to have generated such promising in vivo data in two models of Stop Codon Disease. The fact that a single engineered tRNA acting on the same premature termination codon can show readthrough and protein restoration in two distinct genetic contexts provides support for Alltrna's vision of treating patients carrying the same PTC across different diseases in a given tissue. As a first example, we look forward to developing AP003 through a basket approach as a novel treatment for inborn errors of metabolism affecting the liver."

About AP003
AP003 is a chemically modified, engineered tRNA oligonucleotide encapsulated in a clinically validated, liver-directed lipid nanoparticle that is in development for the treatment of patients with liver Stop Codon Disease that carry an arginine to TGA (Arg-TGA) nonsense mutation in the affected gene. The Arg-TGA mutation occurs when a single base of the arginine-encoding codons, CGA and AGA, mutates to UGA (TGA in DNA), a termination codon for which there is no corresponding amino acid. AP003 is designed to readthrough the premature termination codon to reintroduce arginine into the growing polypeptide chain at the time of RNA-to-protein translation and restore protein production. Arg-TGA is the most frequent nonsense mutation (21-22%) occurring in human genetic diseases.

About Stop Codon Disease
Stop Codon Disease encompasses thousands of rare and common diseases that stem from premature termination codons (PTC) also called nonsense mutations, where the code for an amino acid has been mutated into a premature "stop" codon. 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 approximately 30 million people worldwide. Alltrna is engineering tRNA medicines 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 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 www.alltrna.com.

Media Contacts
Jessica Yingling, Ph.D., Little Dog Communications Inc., [email protected], +1.858.344.8091
Josephine Zorbo, Ph.D., Flagship Pioneering, [email protected]

SOURCE Alltrna