Development of an mRNA replacement therapy for phenylketonuria

• Published in: Molecular therapy. Nucleic acids Vol. 28; pp. 87 - 98
• Main Authors: Perez-Garcia, Carlos G., Diaz-Trelles, Ramon, Vega, Jerel Boyd, Bao, Yanjie, Sablad, Marciano, Limphong, Patty, Chikamatsu, Simon, Yu, Hailong, Taylor, Wendy, Karmali, Priya P., Tachikawa, Kiyoshi, Chivukula, Padmanabh
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14-06-2022; American Society of Gene & Cell Therapy; Elsevier
• Subjects: hepatocytes; lipid nanoparticle; liver; LNP; mRNA; MT: Delivery Strategies; Original; PAH; phenylketonuria; PKU; replacement; therapy; lipid nanoparticle; liver; therapy; PAH; mRNA; PKU; MT: Delivery Strategies; phenylketonuria; replacement; hepatocytes; LNP
• ISSN: 2162-2531; 2162-2531
• DOI: 10.1016/j.omtn.2022.02.020

Phenylketonuria (PKU) is an inborn error caused by deficiencies in phenylalanine (Phe) metabolism. Mutations in the phenylalanine hydroxylase (PAH) gene are the main cause of the disease whose signature hallmarks of toxically elevated levels of Phe accumulation in plasma and organs such as the brain, result in irreversible intellectual disability. Here, we present a unique approach to treating PKU deficiency by using an mRNA replacement therapy. A full-length mRNA encoding human PAH (hPAH) is encapsulated in our proprietary lipid nanoparticle LUNAR and delivered to a Pahenu2 mouse model that carries a missense mutation in the mouse PAH gene. Animals carrying this missense mutation develop hyperphenylalanemia and hypotyrosinemia in plasma, two clinical features commonly observed in the clinical presentation of PKU. We show that intravenous infusion of LUNAR-hPAH mRNA can generate high levels of hPAH protein in hepatocytes and restore the Phe metabolism in the Pahenu2 mouse model. Together, these data establish a proof of principle of a novel mRNA replacement therapy to treat PKU.
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Perez-Garcia-Trelles and colleagues have developed an mRNA replacement therapeutic approach to treat the underlying cause of phenylketonuria in patients carrying a phenylalanine hydroxylase mutation.