Phenylalanine hydroxylase mRNA rescues the phenylketonuria phenotype in mice.

Phenylketonuria (PKU) is an inborn error of metabolism caused by a deficiency in functional phenylalanine hydroxylase (PAH), resulting in accumulation of phenylalanine (Phe) in patients' blood and organs. Affected patients encounter severe developmental delay, neurological deficits, and behavioral abnormalities when not treated. Early diagnosis and treatment are extremely important; newborn screening programs have been implemented in most countries to ensure early identification of patients with PKU. Despite available treatment options, several challenges remain: life-long adherence to a strict diet, approval of some medications for adults only, and lack of response to these therapies in a subpopulation of patients. Therefore, there is an urgent need for treatment alternatives. An mRNA-based approach tested in PKU mice showed a fast reduction in the accumulation of Phe in serum, liver and brain, the most significant organ affected. Repeated injections of LNP-formulated mouse PAH mRNA rescued PKU mice from the disease phenotype for a prolonged period of time. An mRNA-based approach could improve the quality of life tremendously in PKU patients of all ages by replacing standard-of-care treatments.
Competing Interests: CW-T and FC-T are salaried employees of CureVac AG, Tübingen, Germany. NH was salaried employee of CureVac AG, Tübingen, Germany at the beginning of the project; and is salaried employee of Atriva Therapeutics GmbH, Tübingen, Germany. The authors declare that this study received funding from CureVac AG. The funder had the following involvement in the study: study design, collection, analysis, interpretation of data, the writing of this article, and the decision to submit it for publication. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2022 Cacicedo, Weinl-Tenbruck, Frank, Limeres, Wirsching, Hilbert, Pasha Famian, Horscroft, Hennermann, Zepp, Chevessier-Tünnesen and Gehring.)