Mucopolysaccharidosis Type VII (MPS VII) is one of ten human heritable lysosomal storage diseases (LSD's). MPS VII mice and human patients suffer cognitive dysfunction, reduced hearing and sight, skeletal defects, poor joint mobility, hepatosplenomega1y, and early death. The lysosomal enzyme, beta-glucuronidase (GUSB), involved in degradation of glycosaminoglycans (GAG's) is absent in MPS VII. Enzyme replacement therapy (ERT) in the mouse model demonstrates early intervention is essential to attenuate skeletal deformities and progressive learning defects. Continuous infusions can result in anaphylactic shock. Myeloablative bone marrow transplantation (BMT) alleviates disease in visceral organs, but poorly corrects the brain. Mild myeloablation is disruptive to normal brain and skeletal development and increases morbidity in neonatal recipients. Murine MPS VII provides a model to test treatment efficacy pathology), dissemination of GUSB+ donor cells (histochemistry), levels of donor enzyme (biochemistry), and functional correction (bone density, Morris water maze, retinograms, sterility, etc.). We have shown that, in the absence of myeloablation, high-dose syngeneic BMT in neonatal MRS VII mice is therapeutic in visceral and osteoid tissues. Human patients often require allogeneic BMT due to the unavailability of a matched donor. Subsequent complications are GvHD and HvGD.
The specific aims of this study test the hypotheses that in non-ablated MRS VII neonates: (1) immature tissues such as umbilical cord blood (UCB) or fetal liver (FL) have an engrafiment advantage compared to adult bone marrow (ABM) due to reduced immunogenicity.This will be examined by competitive repopulation of allogeneic FL and ABM after prior syngeneic titration to remove stem cell (SC) content and proliferation affects that give FL competitive advantage; (2) blockage of the T cell costimulatory pathway can lead to increased frequency and/or levels of allogeneic engraftment in non-myeloablated recipients and donor lymphocyte infusion (DLI) can amplify allografts. MPS VII recipients will receive anti-CD 154 antibody and/or CTLA-4Ig fusion protein and GUSB allogeneic cells. Engrafted mice will be treated with donor- matched lymphocytes to competitively expand the donor graft; (3) GUSB+ SC from the brain, ABM, or FL can expand post brain ventricle implantation, reduce lysosomal storage, and improve cognitive function. Plasticity will be examined by coculture of SC from ABM and FL with neurospheres and brain SC with marrow stroma. Differentiation capacity will be compared to directly brain implanted SC. Behavioral studies will determine long-term neurological function.
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