Low therapeutic threshold for hepatocyte replacement in murine phenylketonuria

Kelly Hamman, Heather Clark, Eugenio Montini, Muhsen Al-Dhalimy, Markus Grompe, Milton Finegold, Cary Harding

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Phenylalanine homeostasis in mammals is primarily controlled by liver phenylalanine hydroxylase (PAH) activity. Inherited PAH deficiency (phenylketonuria or PKU) leads to hyperphenylalaninemia in both mice and humans. A low level of residual liver PAH activity ensures near-normal dietary protein tolerance with normal serum phenylalanine level, but the precise threshold for normal phenylalanine clearance is unknown. We employed hepatocyte transplantation under selective growth conditions to investigate the minimal number of PAH-expressing hepatocytes necessary to prevent hyperphenylalaninemia in mice. Serum phenylalanine levels remained normal in mice exhibiting nearly complete liver repopulation with PAH-deficient hepatocytes (enu2 mice, a model of human PKU, yielded a significant decrease in serum phenylalanine (

Original languageEnglish (US)
Pages (from-to)337-344
Number of pages8
JournalMolecular Therapy
Volume12
Issue number2
DOIs
StatePublished - Aug 2005

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Phenylketonurias
Phenylalanine Hydroxylase
Phenylalanine
Hepatocytes
Liver
Serum
Therapeutics
Dietary Proteins
Mammals
Homeostasis
Transplantation
Growth

Keywords

  • Hepatocyte transplantation
  • Mouse model
  • Phenylalanine
  • Phenylketonuria

ASJC Scopus subject areas

  • Molecular Biology

Cite this

Low therapeutic threshold for hepatocyte replacement in murine phenylketonuria. / Hamman, Kelly; Clark, Heather; Montini, Eugenio; Al-Dhalimy, Muhsen; Grompe, Markus; Finegold, Milton; Harding, Cary.

In: Molecular Therapy, Vol. 12, No. 2, 08.2005, p. 337-344.

Research output: Contribution to journalArticle

Hamman, Kelly ; Clark, Heather ; Montini, Eugenio ; Al-Dhalimy, Muhsen ; Grompe, Markus ; Finegold, Milton ; Harding, Cary. / Low therapeutic threshold for hepatocyte replacement in murine phenylketonuria. In: Molecular Therapy. 2005 ; Vol. 12, No. 2. pp. 337-344.
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