iScience· 2026Q1
Construction of a self-amplifying mRNA-LNP complex for phenylalanine hydroxylase and its efficacy evaluation in gene therapy for phenylketonuria
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- Q1SCImago
- 2026year
Short summary
A self-amplifying mRNA (saRNA) delivered via lipid nanoparticles (LNPs) achieved sustained phenylalanine hydroxylase (PAH) activity for 14 days in mice with phenylketonuria (PKU), requiring one-sixth the dose of conventional mRNA and showing no toxicity.
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Key points
- Self-amplifying mRNA (saRNA) delivered via lipid nanoparticles (LNPs) effectively restored phenylalanine hydroxylase (PAH) activity in a mouse model of phenylketonuria (PKU).
- The saRNA formulation achieved comparable efficacy to conventional mRNA but at one-sixth the dose.
- Physiological phenylalanine levels were maintained for 14 days post-single injection with saRNA, compared to transient reductions with conventional mRNA.
- Repeated saRNA administration showed no detectable immunogenicity or hepatic toxicity.
AI-generated from the title and abstract; the full text is not read.
Abstract
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.
The authors' abstract, as published at the source. iScience, 2026 · DOI ↗
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Field: Clinical Biochemistry
Clinical BiochemistryBiochemistry, Genetics and Molecular Biology