The mucopolysaccharidoses, a group of inherited metabolic disorders resulting from deficiencies of lysosomal enzymes involved in glycosaminoglycan (GAG) degradation. Mucopolysaccaridosis type IH (MPS IH) (Hurler syndrome) is considered to represent the prototypical MPS disease. Clinical features include severe mental retardation with hepatosplenomegaly, dysostosis multiplex, corneal clouding, cardiac involvement and death in early childhood. Within the first few weeks of life, signs of GAGs accumulation have been noted in patients with MPS IH. BMT can reduce somatic symptomatology. However, the skeletal and neurological complications have been more refractory to correction. We have observed that MPS IH patients appear to be at increased risk for GVHD and graft failure as compared to leukemia patients. We hypothesize that the accumulation of GAGs in GVHD target tissues such as the liver, colon, skin, and lung serve as immunogens for donor T cells.
In aim 1, we will determine whether MPS IH murine recipients are at increased risk for GVHD or graft failure due to the accumulation of GAGs in multiple organ systems.
In aim 2, we will determine whether in utero transplantation (IUT) will offer the maximal opportunity for metabolic correction since GAGs will not have accumulated and donor cells may gain access to priveldged sites such as the CNS. We hypothesize that the common link between skeletal and hematopoietic systems lies within the mesenchymal stem cell (MSC). MSC produce bone, cartilage and fibrous tissue and perhaps astrocytes in vivo and can generate osteoblast-like cells, adipocytic, myocytes, fibroblastic cells, and stroma, the latter of which will support hematopoiesis.
In aim 3, we will determine whether the administration of MSCs will provide superior alloengraftment without GVHD as well as correction of the skeletal system and CNS defects in MPS IH recipients. Thus, the collective proposed studies will address fundamental issues which limit metabolic correction of MPS IH using knockout mice made uniquely available to us for these studies. Data generated may guide future clinical trials designed to optimize therapy of MPS IH patients.
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