Low therapeutic threshold for hepatocyte replacement in murine phenylketonuria

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

Research output: Contribution to journalArticlepeer-review

39 Scopus citations


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 (<5% residual wild-type liver PAH activity). Conversely, transplantation of PAH-positive hepatocytes into PAH-deficient Pahenu2 mice, a model of human PKU, yielded a significant decrease in serum phenylalanine (<700 μM) when liver repopulation exceeded approximately 5%. These data suggest that restoration of phenylalanine homeostasis requires PAH activity in only a minority of hepatocytes.

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


  • Hepatocyte transplantation
  • Mouse model
  • Phenylalanine
  • Phenylketonuria

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery


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