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.
Original language | English (US) |
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Pages (from-to) | 1274-1283 |
Number of pages | 10 |
Journal | Human Gene Therapy |
Volume | 30 |
Issue number | 10 |
DOIs | |
State | Published - Oct 2019 |
Keywords
- base editing
- gene delivery
- liver gene therapy
- nonviral minicircle vector
- rAAV
ASJC Scopus subject areas
- Molecular Medicine
- Molecular Biology
- Genetics