Liver repopulation mediated by hematopoietic stem cells (HSC) is a novel approach to the treatment of rare inborn errors of metabolism for which contemporary therapy has been less than satisfactory.
The specific aim of this project is to explore and develop HSC-mediated therapeutic liver repopulation as a potential treatment for murine phenylketonuria (PKU). Wild type murine HSC will be transplanted into phenylalanine hydroxylase (PAH) deficient Pahenu2 mice, a model of human PKU, under the necessary proliferative and growth selective conditions to induce liver repopulation. Our hypothesis is that liver repopulation with PAHexpressing hepatocytes derived from wild type HSC will correct hyperphenylalaninemia in Pahenu2 mice. Successful liver repopulation requires both a stimulus for hepatocyte proliferation and a selective growth advantage for donor cells. The central challenge in this project is to successfully induce these conditions in the Pahenu2 mouse using exogenous means. This problem will be attacked in three stages. First, wild type bone marrow will be transplanted into mice that lack both PAH and fumarylacetohydrolase (FAH) activity. FAH deficiency in the host provides an inherent stimulus for liver regeneration and a selective growth advantage for FAH+ donor cells. This experiment will evaluate whether HSC-mediated liver repopulation can correct liver PAH deficiency. To explore an exogenous growth stimulus that would promote liver repopulation, Pahenu2 mice will be injected with retrorscine, a DNA alkylating agent that arrests the hepatocyte cell cycle, prior to hepatocyte transplantation. Finally, retrorscine-mediated growth selection will be used to promote HSC-mediated liver repopulation in Pahenu2 mice following wild type bone marrow transplant. The overall goal of the project is to explore HSC-mediated liver repopulation as treatment for rare inborn errors of metabolism using murine PKU as a model system. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HL078850-02
Application #
7002663
Study Section
Special Emphasis Panel (ZRG1-GNM (02))
Program Officer
Thomas, John
Project Start
2005-01-01
Project End
2007-11-30
Budget Start
2005-12-01
Budget End
2007-11-30
Support Year
2
Fiscal Year
2006
Total Cost
$147,452
Indirect Cost
Name
Oregon Health and Science University
Department
Genetics
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Arnold, Georgianne L; Van Hove, Johan; Freedenberg, Debra et al. (2009) A Delphi clinical practice protocol for the management of very long chain acyl-CoA dehydrogenase deficiency. Mol Genet Metab 96:85-90
Harding, Co (2008) Progress toward cell-directed therapy for phenylketonuria. Clin Genet 74:97-104