Journal of Inherited Metabolic Disease

, Volume 33, Issue 6, pp 681–687

Therapeutic liver repopulation for phenylketonuria

Advances and Challenges in PKU

DOI: 10.1007/s10545-010-9099-1

Cite this article as:
Harding, C.O. & Gibson, K.M. J Inherit Metab Dis (2010) 33: 681. doi:10.1007/s10545-010-9099-1


Problems with long-term dietary compliance in phenylketonuria (PKU) necessitate the development of alternative treatment approaches. Therapeutic liver repopulation with phenylalanine hydroxylase (PAH)-expressing cells following hepatocyte or haematopoietic stem cell transplantation has been investigated as a possible novel treatment approach for PKU. Successful therapeutic liver repopulation requires both a stimulus for liver regeneration at the time of cell transplantation and a selective growth advantage for the PAH+ donor cells. Unfortunately, wild-type PAH+ hepatocytes do not enjoy any growth advantage over PAH− cells. Successful correction of hyperphenylalaninemia following therapeutic liver repopulation has been accomplished only in an animal model that yields a selective advantage for the donor cells. Haematopoietic stem cell (HSC)-mediated therapeutic liver repopulation has not been reported in any hyperphenylalaninemic system, and the success of HSC-mediated liver repopulation for PKU may be limited by the slow kinetics of this approach. If therapeutic liver repopulation is to be employed successfully in humans with PKU, an effective method of providing a selective growth advantage for the donor cells must be developed. If this can be achieved, liver repopulation with 10–20% wild-type hepatocytes will likely completely normalize Phe clearance in individuals with PKU.



Enzyme Commission


Fumarylacetoacetate hydrolase


Haematopoietic stem cell


Online Mendelian Inheritance in Man database


Phenylalanine hydroxylase





Copyright information

© SSIEM and Springer 2010

Authors and Affiliations

  1. 1.Department of Molecular and Medical Genetics, and Department of PediatricsOregon Health & Science UniversityPortlandUSA
  2. 2.Department of Biological SciencesMichigan Technological UniversityHoughtonUSA

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