MARROW TRANSPLANT THERAPY FOR MUCOPOLYSACCHARIDOSIS

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We propose to employ a feline model of a lysosomal storage disease, mucopolysaccharidosis VI [arylsulfatase B (ASB) deficiency], to investigate prospectively the degree to which various clinicopathologic and biochemical manifestations of this glycosaminoglycans (GAG) storage disease are prevented, stabilized or corrected through allogeneic bone marrow transplantation (BMT). We have established a breeding colony of mucopolysaccharidosis VI (MPS VI)-affected (homozygous) and carrier (heterozygous) cats. In our initial studies, we have corrected leukocyte arylsulfatase B deficiency in 3 of 3 cats by BMT. Following bone marrow transplantation, many of the clinical features related to excess GAG storage, e.g. corneal clouding, facial dysmorphia, inability to ambulate, and excess urinary excretion of GAG have been reversed after donor-origin, ASB-competent leukocytes have become engrafted. We propose to extend the above observations by conducting additional allogeneic bone marrow transplants in MPS VI affected cats to determine the mechanism by which BMT may prevent, stabilize, or reverse manifestations of MPS VI and the importance of age of MPS-affected individual at time of BMT in influencing the efficacy of this treatment. We will perform BMT in 3 groups of 5 MPS VI-affected cats each at the ages of 12 weeks, 6 months, and 1 year and monitor the following parameters pre- and post-BMT in cats: Radiography and echocardiography and biomicroscopy to evaluate effects of GAG accumulation in skeletal cardiac, corneal, and other visceral tissues; and light and electron microscopy accumulation to localize the intracellular and interstitial of GAG in tissues and lesions; leukocyte, tissue, and urinary arylsulfatase B activity will be assessed to determine whether engraftment has occurred and the degree to which enzyme-competent cells will reverse the GAC accumulation and lesions in affected target tissues. Five MPS VI-affected not treated by BMT cats will be used as controls. We also propose to determine the effect of MPS VI affected allogeneic bone marrow transplantation into unaffected normal recipients to ascertain the extent to which bone marrow derived cells are responsible for glycosaminoglycans degradation in various tissues and organs. Results from these studies will provide information directly pertinent to therapy of lysosomal storage disorders of humans by bone marrow transplantation.