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

Hiu Man Grisch-Chan, Gerald Schwank, Cary O. Harding, Beat Thöny

Research output: Contribution to journalReview articlepeer-review

29 Scopus citations


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 languageEnglish (US)
Pages (from-to)1274-1283
Number of pages10
JournalHuman Gene Therapy
Issue number10
StatePublished - Oct 2019


  • base editing
  • gene delivery
  • liver gene therapy
  • nonviral minicircle vector
  • rAAV

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics


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