ArticleMolecular therapy : the journal of the American Society of Gene Therapy2008
Correction of murine PKU following AAV-mediated intramuscular expression of a complete phenylalanine hydroxylating system.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 61 citations in OpenAlex.
- Nutritional and Therapeutic Strategies in Paediatric Phenylketonuria: A Narrative Literature Review.Nutrients · 2026Review
- Advancing Gene Therapy for Phenylketonuria: From Precision Editing to Clinical Translation.International journal of molecular sciences · 2025Review
- Amelioration of metabolic and behavioral defects through base editing in the PahMolecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- Gene replacement therapies for inherited disorders of neurotransmission: Current progress in succinic semialdehyde dehydrogenase deficiency.Journal of inherited metabolic disease · 2024Review
- State-of-the-art 2023 on gene therapy for phenylketonuria.Journal of inherited metabolic disease · 2024Review
- Enhanced genome editing to ameliorate a genetic metabolic liver disease through co-delivery of adeno-associated virus receptor.Science China. Life sciences · 2022Article
- Clinical, genetic, and experimental research of hyperphenylalaninemia.Frontiers in genetics · 2022Review
- A novel Pah-exon1 deleted murine model of phenylalanine hydroxylase (PAH) deficiency.Molecular genetics and metabolism · 2020Article
- AAV-Mediated CRISPR/Cas9 Gene Editing in Murine Phenylketonuria.Molecular therapy. Methods & clinical development · 2020Article
- Sustained Correction of a Murine Model of Phenylketonuria following a Single Intravenous Administration of AAVHSC15-PAH.Molecular therapy. Methods & clinical development · 2020Article
- The future of gene-targeted therapy for hereditary tyrosinemia type 1 as a lead indication among the inborn errors of metabolism.Expert opinion on orphan drugs · 2020Article
- State-of-the-Art 2019 on Gene Therapy for Phenylketonuria.Human gene therapy · 2019Review
- Comparative genomics provides new insights into the remarkable adaptations of the African wild dog (Lycaon pictus).Scientific reports · 2019Article
- Improved Lentiviral Gene Delivery to Mouse Liver by Hydrodynamic Vector Injection through Tail Vein.Molecular therapy. Nucleic acids · 2018Article
- Blood phenylalanine reduction corrects CNS dopamine and serotonin deficiencies and partially improves behavioral performance in adult phenylketonuric mice.Molecular genetics and metabolism · 2018Article
- Gene Therapy for the Treatment of Neurological Disorders: Metabolic Disorders.Methods in molecular biology (Clifton, N.J.) · 2016Review
- A sensitive assay system to test antisense oligonucleotides for splice suppression therapy in the mouse liver.Molecular therapy. Nucleic acids · 2014Article
- Treatment of phenylketonuria using minicircle-based naked-DNA gene transfer to murine liver.Hepatology (Baltimore, Md.) · 2014Article
- Effects of adeno-associated virus serotype and tissue-specific expression on circulating biomarkers of propionic acidemia.Human gene therapy · 2014Article
- Phenotypic reversion of fair hair upon gene therapy of the phenylketonuria mice.Human gene therapy · 2014Article
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
Abstract
Phenylketonuria (PKU) caused by phenylalanine hydroxylase (PAH) deficiency leads to toxic accumulation of phenylalanine (Phe). PAH is predominantly expressed in liver and its activity requires a supply of tetrahydrobiopterin (BH(4)) cofactor, but we propose that expression of a complete Phe hydroxylating system (PAH plus BH(4) synthetic enzymes) in skeletal muscle will lead to therapeutic reduction of blood Phe levels in Pah(enu2) mice, a model of human PKU. In order to test this hypothesis, we first developed transgenic Pah(enu2) mice that lack liver PAH activity but coexpress, in their skeletal muscle, PAH and guanosine triphosphate cyclohydrolase I (GTPCH). The latter is responsible for the committing enzymatic step in BH(4) biosynthesis. Despite sufficient muscle enzyme expression, these mice remained hyperphenylalaninemic, thereby suggesting that expression of additional BH(4) synthetic enzymes would be necessary. A recombinant triple-cistronic adeno-associated virus-2 (AAV2) pseudotype 1 vector expressing PAH along with GTPCH and 6-pyruvoyltetrahydrobiopterin synthase (PTPS), the next step in BH(4) synthesis, was generated. Injection of this vector into the gastrocnemius muscles of Pah(enu2) mice led to stable and long-term reduction of blood Phe and reversal of PKU-associated coat hypopigmentation. We propose that muscle-directed gene therapy will be a viable alternative treatment approach to PKU and other inborn errors of metabolism.
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