State-of-the-Art 2019 on Gene Therapy for Phenylketonuria

Human Gene Therapy
Hiu Man Grisch-ChanBeat Thöny

Abstract

Phenylketonuria (PKU) is considered to be a paradigm for a monogenic metabolic disorder but was never thought to be a primary application for human gene therapy due to established alternative treatment. However, somewhat unanticipated improvement in neuropsychiatric outcome upon long-term treatment of adults with PKU with enzyme substitution therapy might slowly change this assumption. In parallel, PKU was for a long time considered to be an excellent test system for experimental gene therapy of a Mendelian autosomal recessive defect of the liver due to an outstanding mouse model and the easy to analyze and well-defined therapeutic end point, that is, blood l-phenylalanine concentration. Lifelong treatment by targeting the mouse liver (or skeletal muscle) was achieved using different approaches, including (1) recombinant adeno-associated viral (rAAV) or nonviral naked DNA vector-based gene addition, (2) genome editing using base editors delivered by rAAV vectors, and (3) by delivering rAAVs for promoter-less insertion of the PAH-cDNA into the Pah locus. In this article we summarize the gene therapeutic attempts of correcting a mouse model for PKU and discuss the future implications for human gene therapy.

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Citations

Oct 2, 2019·Human Gene Therapy·Hildegard BüningFederico Mingozzi
Jun 9, 2020·Journal of Inherited Metabolic Disease·Hidde A ZittersteijnRob C Hoeben
Aug 22, 2020·Médecine sciences : M/S·Arnaud WiedemannFeillet François
Jun 12, 2020·Molecular Frontiers Journal·Cary O Harding
Jun 11, 2021·Science Translational Medicine·Anne VonadaMarkus Grompe

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Methods Mentioned

BETA
deamination
transfection

Clinical Trials Mentioned

NCT03952156

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