Development of an mRNA replacement therapy for phenylketonuria

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...

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Bibliographic Details
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
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Summary:	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. [Display omitted] 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors have contributed equally
ISSN:	2162-2531 2162-2531
DOI:	10.1016/j.omtn.2022.02.020