Post-natal marrow or peripheral blood stem cell transplantation can effectively treat many genetic disorders which involve blood cells, but is not universally available because of its high cost, moderate risk, and the lack of suitable donors of hematopoietic stem cells. As importantly, in some diseases, such as the lysosomal storage disorders, neurologic toxicity occurs by birth, which is not reversible by transplantation. The investigators plan to study the in utero therapy of alpha-mannosidosis in cats. Besides transplanting hematopoietic stem cells from adult cats to domestic cat fetuses, they propose two novel approaches, the in utero transplantation of macrophage precursor cells and in utero gene transfer (with FeLV-pseudotyped, retroviral vectors containing marker genes and/or MANB cDNA). The investigators will also study the kinetics of tissue macrophage engraftment in a murine ROSA26 transplantation model, to identify the immediate precursor cell of microglia in brain, Kuppffer cells in liver, and alveolar macrophages in lung. The investigators will define the cellular mechanisms which mediate lodgment. The results of experiments in this murine model will be applied in the in utero transplantation studies of alpha-mannosidosis in cats. The investigators are hopeful that these studies will provide alternative approaches for the therapy of lysosomal storage disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK049652-06
Application #
6177199
Study Section
Special Emphasis Panel (ZRG3-PBC (01))
Program Officer
Mckeon, Catherine T
Project Start
1994-09-30
Project End
2003-08-31
Budget Start
2000-09-01
Budget End
2001-08-31
Support Year
6
Fiscal Year
2000
Total Cost
$247,810
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Abkowitz, Janis L; Sabo, Kathleen M; Yang, Zhantao et al. (2009) In utero transplantation of monocytic cells in cats with alpha-mannosidosis. Transplantation 88:323-9
Ellinwood, N Matthew; Vite, Charles H; Haskins, Mark E (2004) Gene therapy for lysosomal storage diseases: the lessons and promise of animal models. J Gene Med 6:481-506
Vite, Charles H; Passini, Marco A; Haskins, Mark E et al. (2003) Adeno-associated virus vector-mediated transduction in the cat brain. Gene Ther 10:1874-81
Vite, C H; McGowan, J C; Braund, K G et al. (2001) Histopathology, electrodiagnostic testing, and magnetic resonance imaging show significant peripheral and central nervous system myelin abnormalities in the cat model of alpha-mannosidosis. J Neuropathol Exp Neurol 60:817-28
Sun, H; Yang, M; Haskins, M E et al. (1999) Retrovirus vector-mediated correction and cross-correction of lysosomal alpha-mannosidase deficiency in human and feline fibroblasts. Hum Gene Ther 10:1311-9
Abkowitz, J L; Taboada, M R; Sabo, K M et al. (1998) The ex vivo expansion of feline marrow cells leads to increased numbers of BFU-E and CFU-GM but a loss of reconstituting ability. Stem Cells 16:288-93
Kennedy, D W; Abkowitz, J L (1998) Mature monocytic cells enter tissues and engraft. Proc Natl Acad Sci U S A 95:14944-9
Kennedy, D W; Abkowitz, J L (1997) Kinetics of central nervous system microglial and macrophage engraftment: analysis using a transgenic bone marrow transplantation model. Blood 90:986-93