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Therapeutic liver repopulation for phenylketonuria

  • Advances and Challenges in PKU
  • Published:
Journal of Inherited Metabolic Disease

Abstract

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.

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Abbreviations

EC:

Enzyme Commission

FAH:

Fumarylacetoacetate hydrolase

HSC:

Haematopoietic stem cell

OMIM:

Online Mendelian Inheritance in Man database

PAH:

Phenylalanine hydroxylase

Phe:

Phenylalanine

PKU:

Phenylketonuria

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Acknowledgements

This work has been supported by grants from the US National Institute for Diabetes, Digestive, and Kidney Diseases (NIDDK) and the National Heart, Blood, and Lung Institute. The authors take full responsibility for the content of this meeting report but thank Caudex Medical (supported by Serono Symposia International Foundation) for their assistance in preparing the initial draft of this report and collating the comments of authors and any other named contributors.

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Authors and Affiliations

  1. Department of Molecular and Medical Genetics, and Department of Pediatrics, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Mail code L103, Portland, OR, 97239, USA

    Cary O. Harding

  2. Department of Biological Sciences, Michigan Technological University, 740 Dow ESE Building, 1400 Townsend Drive, Houghton, MI, 49931-1295, USA

    K. M. Gibson

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  1. Cary O. Harding
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Correspondence to Cary O. Harding.

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Communicated by: Verena Peters

Use of electronic databases: OMIM.

Competing interest: None declared.

Presented at the Serono Symposia International Foundation Meeting, “Advances and Challenges in PKU”, 16–17 January 2009 in Barcelona, Spain.

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Harding, C.O., Gibson, K.M. Therapeutic liver repopulation for phenylketonuria. J Inherit Metab Dis 33, 681–687 (2010). https://doi.org/10.1007/s10545-010-9099-1

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