Alltrna Shows Preclinical Potential of tRNA to Work Across Nonsense Mutations

Rare Daily Staff

Alltrna said new preclinical data showed that the company’s first experimental transfer RNA therapeutic candidate restored protein production to clinically meaningful levels in nonsense mutation disease mouse models for methylmalonic acidemia and phenylketonuria in vivo.

Transfer RNA (tRNA) is a compelling approach to treating rare diseases driven by nonsense mutations because a single therapy has the potential to work across mutations regardless of the gene in which they occur. Nonsense mutations introduce a premature termination codon that that halts the translation of genetic instructions into needed proteins before they are completed. Alltrna refers to these conditions collectively as stop codon disease.

Stop codon disease encompasses thousands of rare and common diseases that stem from premature termination codons, 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 percent 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 premature termination codons and deliver the desired amino acid, thereby restoring the production of the full-length protein.

The company’s experimental therapy AP003 is a chemically modified, engineered tRNA oligonucleotide in a liver-directed lipid nanoparticle that can read through the arginine to TGA (Arg-TGA) premature termination codon. The data were presented at the Nature Conference: RNA at the Bench and Bedside IV at The Salk Institute in La Jolla, California.

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

In a new stop codon disease mouse model of phenylketonuria (PKU), developed by Alltrna, a single dose of AP003 demonstrated phenylalanine hydroxylase (PAH) restoration to 7 percent of wildtype levels within 72 hours, exceeding the clinically relevant 3 percent protein rescue target defined by key opinion leaders. The PAH protein restoration resulted in a meaningful 76 percent 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.

“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 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.”

Photo: Michelle Werner, CEO of Alltrna and CEO-Partner at Flagship Pioneering