The mucopolysaccharidoses (MPS) are heritable lysosomal storage diseases caused by deficiency of acid hydrolases required for the degradation of glycosaminoglycans. The deficiency of beta- glucuronidase causes accumulation of dermatan sulfate, heparan sulfate, and chondroitin sulfate in MPS Type VII (Sly syndrome). Patients progressively develop severe growth and mental retardation and die prematurely. The MPS VII mouse model shares histopathological and clinical features of human MPS VII. The mice are indistinguishable from their normal littermates at birth and are genotyped by either enzyme assays or PCR analysis. The mice become more severely debilitated with increasing age and most die prior to 6 months of age. Transplantation of normal marrow into lethally irradiated adult mutants corrects lysosomal storage in many tissues, prolongs the life span three fold, but skeletal deformities and neuronal storage remain unchanged. Transplantation into irradiated newborns MPS VII mice results in more extensive improvements in bone and joint malformations and better delivery of enzyme to the brain. However, radiation dose dependent cerebellar dysplasia and long bone grow retardation are noted in the recipients. Recently, we have shown that cogenic adult +/+ marrow does implant in newborns without prior irradiation and that donor cells are easily distinguished from null and cross-corrected host cells by histochemistry. Our data indicate the MPS VII mice are excellent models for in utero therapy. The MPS VII mutation is fixed on the C57BL/6J strain, congenic with unique stocks carrying hematopoietic cell markers or single histocompatibility gene differences that are essential to address the questions posed in the RFA. We propose to: Determine the efficacy of normal stem cell transplantation in utero by evaluating the histopathology of adult MPS VII mice; Define the stage of gestation where optimum stem cell proliferation follows engraftment; Identify the location and measure the number of donor hematopoietic precursors post- transplantation; Quantify the effectiveness of donor cells from different sites; and Compare the effectiveness of histocompatible and incompatible adult and fetal donor cells.
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