iScienceSep 23, 2026

Developing and Testing a Self-Boosting mRNA Treatment for Phenylketonuria

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Sep 24, 2026

Abstract

The self-amplifying RNA formulation reduced circulating phenylalanine levels for 14 days after a single injection.

Both self-amplifying RNA (saRNA) and conventional non-replicating mRNA (nr-mRNA) constructs were tested in Pah-knockout mice.
The saRNA formulation required only one-sixth the dose of nr-mRNA to achieve similar efficacy.
While the saRNA maintained physiological phenylalanine levels for 14 days, the nr-mRNA produced only temporary reductions.
Repeated administrations of saRNA were well tolerated with no signs of immune response or liver damage.

Simplified

Phenylketonuria (PKU) is an autosomal recessive disorder caused by deficient phenylalanine hydroxylase (PAH) activity, with current pharmacotherapies showing limited response rates and age-dependent restrictions. We compared two liver-targeted lipid nanoparticle formulations delivering PAH-encoding mRNA-a self-amplifying construct (saRNA) and a conventional non-replicating counterpart (nr-mRNA)-in Pah-knockout mice. Both constructs reduced circulating phenylalanine (Phe) after a single intravenous injection. The saRNA formulation achieved comparable efficacy at one-sixth the nr-mRNA dose and maintained physiological Phe levels for 14 days, whereas nr-mRNA produced only transient reductions. Repeated saRNA administration was well tolerated, with no detectable immunogenicity or hepatic toxicity. These results establish that saRNA-mediated PAH replacement provides sustained activity with substantial dose reduction, overcoming the short-lived effect of non-replicating mRNA. This platform may inform broader strategies for durable enzyme therapy in inherited metabolic diseases requiring liver-restored function.