MARROW TRANSPLANT THERAPY FOR MUCOPOLYSACCHARIDOSIS

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Bone marrow transplantation is a promising therapy for some lysosomal storage disorders in human beings. Donor leukocytes may establish enzyme activity on a continual basis in amounts sufficient to be within normal limits. Allogeneic bone marrow transplants in animals with lysosomal storage diseases will determine the degree by which BMT may prevent, stabilize, or reverse manifestations of various lysosomal storage diseases. We propose to continue to employ a feline model of mucopolysaccharidosis VI (arylsulfatase B deficiency) to investigate prospectively the degree to which various clinical, morphological, and biochemical manifestations of this glycosaminoglycan storage disease are prevented, stabilized, or corrected through allogenic bone marrow transplantation. Long term evaluation of treated animal is necessary to determine if substrate is reduced in liver, cartilage, cornea, and other tissues. Clinical heterogeneity is marked in animals and people with many of the lysosomal storage diseases, making clinical evaluation of the progression of disease subjective. It is proposed to study larger numbers of BMT treated and untreated affected animals to determine if differences are statistically significant. Six MPS VI affected-BMT treated cats, two MPS VI affected-BMT treated cats which autologously recovered their own marrow, and 8 MPS VI affected non BMT treated cats will continue to be monitored. In addition, six 10 weeks old MPS VI affected cats will be transplanted in year 4, and six in year 5, for a total of 18 MPS VI affected-BMT treated cats. Two additional MPS VI affected-non treated controls will be monitored beginning year 4. MPS VI affected cats will be monitored morphologically pre-and at 6 months then yearly post-BMT by radiography, photography, computed tomography, slit lamp biomicroscopy, electroretinography, and light and electron microscopy of liver, brain, cartilage, and skin biopsies and necropsy tissues. MPS VI cats will be monitored biochemically by leukocyte and tissue arylsulfatase B activity and by analysis and characterization of urine, liver, cornea, cartilage and cochlea glycosaminoglycans. Untreated cats will be monitored similarly for comparison. These studies will determine the degree to which enzyme-competent cells will reverse or prevent the glycosaminoglycan accumulation and lesions in affected target tissues. Results from these studies will provide information directly pertinent to therapy of lysosomal storage disorders of humans by either bone marrow transplantation or gene therapy.