期刊
HUMAN GENE THERAPY
卷 30, 期 10, 页码 1274-1283出版社
MARY ANN LIEBERT, INC
DOI: 10.1089/hum.2019.111
关键词
rAAV; nonviral minicircle vector; gene delivery; base editing; liver gene therapy
资金
- Forschungszentrum fur das Kind
- Swiss National Science Foundation [3100A0-105250, CRSII5_ 180257/1, 31003A_160230]
- Wolfermann Nageli Stiftung
- NIH [R01NS080866]
- Swiss National Science Foundation (SNF) [31003A_160230, CRSII5_180257] Funding Source: Swiss National Science Foundation (SNF)
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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