MARROW TRANSPLANT THERAPY FOR MUCOPOLYSACCHARIDOSIS

我们建议使用一种溶酶体储存疾病的猫模型， 粘多糖病VI[芳基硫酸酯酶B(ASB)缺乏症] 不同临床病理和生化指标的前瞻性程度 这种糖胺多聚糖(GAG)储存疾病的表现是 通过异基因骨髓预防、稳定或矫正 移植(BMT)。我们已经建立了一个繁育群体 粘多糖病VI(MPS VI)-受累(纯合子)和携带者 (杂合子)猫。在我们最初的研究中，我们已经纠正了白细胞 骨髓移植发现3只猫中有3只芳基硫酸酯酶B缺乏症。跟随骨髓 移植，许多临床特征与过量的GAG有关 储存，例如角膜混浊，面部变形，无法行走， 供者来源后，GAG的过量尿液排泄被逆转， 具有ASB能力的白细胞已经植入体内。我们建议延长 通过移植额外的异基因骨髓进行上述观察 MPS VI中的移植影响猫以确定BMT的机制 可预防、稳定或逆转MPS VI和 骨髓移植时MPS患者年龄在影响因素中的重要性 这种疗法的疗效。我们将进行3组5 MPS的BMT 分别在12周、6个月和1岁时感染VI病毒的猫和 监测猫骨髓移植前后的以下参数：X光照相 超声心动图和生物显微镜评价GAG的疗效 在骨骼、心脏、角膜和其他内脏组织中蓄积；以及 光镜和电子显微镜积聚以定位细胞内 组织和病变中的GAG和间质；白细胞、组织和 将评估尿芳基硫酸酯酶B的活性以确定 是否发生了植入以及酶活性细胞的程度 将逆转GAC在受影响的靶组织中的积聚和损害。 未接受BMT猫治疗的5只受VI影响的MPS将作为对照。我们 也建议确定MPS VI对同种异体骨的影响 对未受影响的正常受者进行骨髓移植以确定 骨髓来源的细胞在多大程度上负责 糖胺多聚糖在各种组织和器官中的降解。结果来自 这些研究将提供与治疗直接相关的信息。 骨髓移植引起的人类溶酶体储存障碍。

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.