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. ? ? ?
| 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 |
