State of the Art 2019 on Gene therapy for Phenylketonuria.
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, i.e. blood L phenylalanine (L Phe) concentration. Life long treatment by targeting the mouse liver (or skeletal muscle) was achieved using different approaches, including (i) rAAV or non viral naked DNA vector based gene addition, (ii) genome editing using base editors delivered by rAAV vectors, and (iii) by delivering rAAVs for promoter less insertion of the PAH cDNA into the Pah locus. Here we summarize the gene therapeutic attempts of correcting a mouse model for PKU and discuss the future implications for human gene therapy.
Human gene therapy