MARROW TRANSPLANT THERAPY FOR MUCOPOLYSACCHARIDOSIS

骨髓移植是一种有前途的治疗某些溶酶体 人类的记忆障碍 供体白细胞可建立酶 持续的活动，其数量足以在正常范围内 限制. 同种异体骨髓移植在溶酶体动物中的应用 贮藏病害将决定BMT可以预防的程度， 稳定或逆转各种溶酶体贮积病表现。 我们建议继续采用粘多糖沉积症VI的猫模型 （芳基硫酸酯酶B缺乏），以前瞻性地研究 各种临床，形态学和生化表现， 这种糖胺聚糖贮积病被预防、稳定，或 通过同种异体骨髓移植纠正。 长期 需要对处理的动物进行评价，以确定底物是否 肝脏、软骨、角膜和其他组织中的含量减少。 临床 在动物和人中，异质性是显著的， 储存疾病，对疾病进展进行临床评价 主观. 建议研究更多数量的BMT治疗和未治疗的受影响患者， 动物以确定差异是否具有统计学显著性。 6个MPS VI受累-BMT给药猫，2只MPS VI受累-BMT给药猫， 自体骨髓回收，8例MPS VI累及非BMT 将继续监测接受治疗的猫。 此外，6只10周大的 MPS VI受影响的猫将在第4年移植，第5年移植6只， 共18只MPS VI受影响的BMT给药猫。 两个额外MPS VI 从第4年开始监测受影响的-未处理的对照组。 MPs VI 受影响的猫将在术前和6个月时进行形态学监测，然后 BMT后每年通过X线摄影、摄影、计算机断层扫描、裂隙灯检查 生物显微镜，视网膜电图，光学和电子显微镜， 肝、脑、软骨和皮肤活组织检查和尸检组织。 MPs VI 将通过白细胞和组织芳基硫酸酯酶B对猫进行生化监测 活性，并通过分析和表征尿液，肝脏，角膜， 软骨和耳蜗糖胺聚糖。 将监测未给药猫 类似的比较。 这些研究将决定 酶活性细胞将逆转或阻止糖胺聚糖 受影响靶组织中的蓄积和病变。 从这些 研究将提供直接相关的信息，以治疗溶酶体 通过骨髓移植或基因治疗的人类储存障碍 疗法

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.