Phenylketonuria (PKU) is an autosomal recessive disease caused by the abnormal metabolism of phenylalanine (Phe). PKU is caused by a mutation in the phenylalanine hydroxylase (PAH) gene. This gene produces a liver enzyme that converts dietary phenylalanine into Tyr, a key precursor for the synthesis of neurotransmitters such as dopamine, epinephrine, or norepinephrine.

PKU is a congenital defect brought on by insufficient metabolism of phenylalanine. The condition, which is characterized by excessive phenylalanine buildup in plasma, the brain, and other organs and results in permanent mental disability, is mostly caused by mutations in the PAH gene.

The homologous tetramer protein PAH requires the catalytic activity of cofactor tetrahydrobiopterin (BH4) to play its role. The defects of BH4 can also lead to mild PKU. With the support of a diet that limits Phe, oral administration of KUVAN, a synthetic form of BH4, normalizes circulating Phe levels in people with moderate PKU. Polyethylene glycolase (Palynziq), the only approved drug for treating the classical PKU, has unknown doses and side effects.

The results provide proof of the principle of a new mRNA replacement therapy for PKU in a recent publication titled “Development of an mRNA replacement therapy for phenylketonuria” published in the journal Molecular Therapy: Nucleic Acids.

Here, the researchers propose using messenger RNA replacement therapy as a unique approach for treating PKU deficiency. The full-length messenger ribonucleic acid encoding human PAH (HPAH)was encapsulated in proprietary lipid nanoparticles LUNAR and given to the Pahenu2 mouse model, which has a missense mutation in the mouse PAH gene.

Animals with this missense mutation will experience hyperphenylalaninemia and hypotyrosinemia in plasma, which are two PKU common clinical features in animal models. The researchers found that giving Pahenu2 mice intravenous injections of LUNAR-hPAH mRNA could produce high levels of hepatocyte hPAH protein and restore Phe metabolism.

The researchers’ results here support the use of a new PAH mRNA replacement therapy as an effective PKU treatment. This treatment has the potential to reduce the need for dietary restrictions, which may improve the lives of PKU patients by restoring Phe metabolism and lowering plasma toxic Phe levels, thereby reducing the risk of any adverse events.