Certain heritable childhood diseases respond well to the transplantation of hematopoietic stem cells (HSC). Transplantation, even with cord blood (CB) cells, is not always successful due to graft loss, graft versus host disease (GVHD), myeloablative toxicity, and disease related mortality. Our goal is to improve therapy in newborn mouse models of progressive childhood diseases using techniques that sustain long term engraftment without GVHD or extensive myeablation. We study Mucopolysaccharidosis type VII (MMPS VII), one of family of lysosomal storage diseases resulting in bone dysplasia, mental disabilities, and early death. While the beta-glucuronidase (beta-GUS) deficiency in MPS VII can be cross-corrected post-myeloablation by tissue macrophages from donor +/+ or beta-GUS-transduced MPS VII HSC, extensive newborn myeloablation reduces bone growth and scrambles brain architecture. A new treatment high dose injections of +/+ adult marrow HSC into non- ablated MPS VII neonates dramatically improves bone growth and brain function. Unfortunately, the beta-GUS+ graft is gradually lost from newborn but not from adult recipients. We believe that the adult donor cells are either incompatible with the newborn environment or out competed by rapidly expanding host cells. Genetic markers allow us to test the alternatives and to compare and quantify implantation, amplification, and distribution of donor and host cells. The hypothesis we address is that chimerism after neonatal treatment can be maintained and provides long term storage correction and functional improvement. We will use MPS VII neonatal recipients: determine whether the environment provides a selective advantage for fetal/newborn versus adult +/+ cells; monitor the amplification of adult beta-GUS+ donor and of null host cells; characterize effects on long term beta-GUS+ repopulation of pre-treatment mobilization/loss of host HSC; determine whether long-lasting multi-tissue chimerism results from enriched HSC injection; compare the curative nature of compatible and incompatible CB cells; and characterize the therapeutic effects of donor beta-GUS+ pure-macrophages derived in vitro from +/+ HSC or from MPS VII gene transduced HSC.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Medical Biochemistry Study Section (MEDB)
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Mckeon, Catherine T
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Jackson Laboratory
Bar Harbor
United States
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