ArticleMolecular genetics and metabolism2004
The fate of intravenously administered tetrahydrobiopterin and its implications for heterologous gene therapy of phenylketonuria.
Article in Molecular genetics and metabolism, 2004. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 22 citations in OpenAlex.
- The Generation of an Induced Pluripotent Stem Cell Line from a Patient with Phenylketonuria.International journal of stem cells · 2025Article
- Diagnostic and predictive values of circulating tetrahydrobiopterin levels as a novel biomarker in patients with thoracic and abdominal aortic aneurysms.Redox biology · 2022Article
- High dose sapropterin dihydrochloride therapy improves monoamine neurotransmitter turnover in murine phenylketonuria (PKU).Molecular genetics and metabolism · 2016Article
- Acute tetrahydrobiopterin supplementation attenuates sympathetic vasoconstrictor responsiveness in resting and contracting skeletal muscle of healthy rats.Physiological reports · 2014Article
- Protein stability and in vivo concentration of missense mutations in phenylalanine hydroxylase.Proteins · 2012Article
- New era in treatment for phenylketonuria: Pharmacologic therapy with sapropterin dihydrochloride.Biologics : targets & therapy · 2010Article
- Comparison of adeno-associated virus pseudotype 1, 2, and 8 vectors administered by intramuscular injection in the treatment of murine phenylketonuria.Human gene therapy · 2010Article
- Correction of kinetic and stability defects by tetrahydrobiopterin in phenylketonuria patients with certain phenylalanine hydroxylase mutations.Proceedings of the National Academy of Sciences of the United States of America · 2004Article
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Tetrahydrobiopterin (BH(4)) is a required cofactor for the enzymatic activity of phenylalanine hydroxylase (PAH) and is synthesized de novo from GTP in several tissues. Heterologous expression of PAH in tissues other than liver is a potential novel therapy for human phenylketonuria that is completely dependent upon BH(4) supply in the PAH-expressing tissue. Previous experiments with liver PAH-deficient transgenic mice that expressed PAH in skeletal muscle demonstrated transient correction of hyperphenylalaninemia only with hourly parenteral BH(4) administration. In this report, the fate of intravenously administered BH(4) is examined. The conclusions are that (1) BH(4) administered intravenously is rapidly taken up by liver and kidney, and (2) uptake of BH(4) into muscle is relatively low. The levels of BH(4) achieved in skeletal muscle following IV injection are only 10% of the amount expected were BH(4) freely and equally distributed across all tissues. The half-life of BH(4) in muscle is approximately 30 min, necessitating repeated injections to maintain muscle BH(4) content sufficient to support phenylalanine hydroxylation. The efficacy of heterologous muscle-directed gene therapy for the treatment of PKU will likely be limited by the BH(4) supply in PAH-expressing muscle.
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Registered trials
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