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

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.

Keywords: base editing; gene delivery; liver gene therapy; nonviral minicircle vector; rAAV.

Figure 1.

Phenotype reversion of fair hair upon gene therapy of the PKU mice. Reversion from brown to black coat of treated (C57Bl/6) PKU mice as depicted in the figure is a phenomenon that can be seen from gene therapy or any other treatment, including dietary or pegvaliase treatment. Not only mice but also patients with untreated PKU exhibit blond hair and fair skin. Tyrosine that is needed to make melanin, the pigment that gives skin and hair its coloring, is limited under untreated PKU conditions and the corresponding enzyme, tyrosinase, is competitively inhibited by elevated phenylalanine levels. The figure is reproduced with permission from Viecelli et al. wherein mice were treated with nonviral naked DNA vector expressing phenylalanine hydroxylase on the right, wild type mice untreated on the left, and PKU mice untreated in the middle. PKU, phenylketonuria. Color images are available online.