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

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.

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

Inan 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 systemrestored in vivo protein levels of methylmalonyl-CoA mutase (MMUT) toapproximately 25% of wildtype levels at Day 4, well above the 1-2% proteinrescue considered to be clinically meaningful in MMA by key opinion leaders.Protein levels remained above 1-2% of wildtype 14 days after dosing, which wasthe longest time point tested.

Ina new Stop Codon Disease mouse model of PKU, developed by Alltrna, a singledose of AP003 demonstrated phenylalanine hydroxylase (PAH) restoration to 7% ofwildtype levels within 72 hours, exceeding the clinically relevant 3% proteinrescue target defined by key opinion leaders. Further, this PAH proteinrestoration 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 thehallmark elevated Phe levels observed in PKU.

"Basedon tRNA's critical role in protein translation, a single tRNA medicine isuniquely positioned to address multiple diseases that have a shared mutation.We are excited to see that our engineered tRNA can in fact achieve significantrestoration of protein production above clinically relevant target levels inboth MMA and PKU, where a premature termination codon would otherwise create atruncated or missing protein," said Chris Henderson, Ph.D., ChiefScientific Officer of Alltrna. "In addition, to our knowledge, these arethe first preclinical data with a tRNA candidate demonstrating that proteinrestoration 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 invivo data in two models of Stop Codon Disease. The fact that a singleengineered tRNA acting on the same premature termination codon can showreadthrough and protein restoration in two distinct genetic contexts providessupport for Alltrna's vision of treating patients carrying the same PTC acrossdifferent diseases in a given tissue. As a first example, we look forward todeveloping AP003 through a basket approach as a novel treatment for inbornerrors of metabolism affecting the liver."

AboutAP003
AP003 is a chemically modified, engineered tRNA oligonucleotideencapsulated in a clinically validated, liver-directed lipid nanoparticle thatis in development for the treatment of patients with liver Stop Codon Diseasethat 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 thereis no corresponding amino acid. AP003 is designed to readthrough the prematuretermination codon to reintroduce arginine into the growing polypeptide chain atthe time of RNA-to-protein translation and restore protein production. Arg-TGAis the most frequent nonsense mutation (21-22%) occurring in human geneticdiseases.

AboutStop Codon Disease
Stop Codon Disease encompasses thousands of rare and commondiseases that stem from premature termination codons (PTC) also called nonsensemutations, where the code for an amino acid has been mutated into a premature"stop" codon. This results in a truncated or shortened proteinproduct 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 engineeringtRNA medicines that can read these PTC mutations and deliver the desired aminoacid, thereby restoring the production of the full-length protein.

AboutAlltrna
Alltrna unlocks tRNA biology to treat disease. The company'splatform incorporates AI/ML tools to develop and deliver diverse programmablemolecules with broad therapeutic potential. Alltrna has an unprecedentedopportunity to advance a single tRNA medicine to readthrough premature stopcodons and unify treatment across a wide range of diseases with the sameunderlying genetic mutations. Alltrna was founded in 2018 by FlagshipPioneering. For more info, visit www.alltrna.com.

Media Contacts
Jessica Yingling, Ph.D., Little Dog Communications Inc., jessica@litldog.com,+1.858.344.8091
Josephine Zorbo, Ph.D., Flagship Pioneering, Jzorbo@flagshippioneering.com

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