RNA solution for a genetic problem
Phenylketonuria is a classic example of the benefit of newborn metabolic screening: It is a single-gene disease that can be detected at birth, and its neurological effects can be prevented by dietary therapy. Unfortunately, this is not always straightforward because the disease-causing mutations in phenylalanine hydroxylase vary between patients and affect the severity of the phenotype, such that some patients’ symptoms do not fully respond to the available interventions. Li et al. identified two long noncoding RNAs, one in mice and one in humans, that interact with phenylalanine hydroxylase and modulate its function (see the Perspective by Ben-Tov Perry and Ulitsky). Administration of modified RNAs mimicking their effects ameliorated the disease phenotype in mouse models of phenylketonuria.
Science, aba4991, this issue p. 662; see also abj7969, p. 623
Abstract
The functional role of long noncoding RNAs (lncRNAs) in inherited metabolic disorders, including phenylketonuria (PKU), is unknown. Here, we demonstrate that the mouse lncRNA Pair and human HULC associate with phenylalanine hydroxylase (PAH). Pair-knockout mice exhibited excessive blood phenylalanine (Phe), musty odor, hypopigmentation, growth retardation, and progressive neurological symptoms including seizures, which faithfully models human PKU. HULC depletion led to reduced PAH enzymatic activities in human induced pluripotent stem cell–differentiated hepatocytes. Mechanistically, HULC modulated the enzymatic activities of PAH by facilitating PAH-substrate and PAH-cofactor interactions. To develop a therapeutic strategy for restoring liver lncRNAs, we designed GalNAc-tagged lncRNA mimics that exhibit liver enrichment. Treatment with GalNAc-HULC mimics reduced excessive Phe in Pair−/− and PahR408W/R408W mice and improved the Phe tolerance of these mice.