MARROW TRANSPLANT THERAPY FOR MUCOPOLYSACCHARIDOSIS

我们建议采用一种溶酶体贮积病的猫模型， 粘多糖沉积症VI [芳基硫酸酯酶B（AS B）缺乏]，以研究 前瞻性地，各种临床病理和生化 这种糖胺聚糖（GAG）储存病的表现是 通过同种异体骨髓预防、稳定或纠正 移植（BMT）。 我们建立了一个繁殖地 粘多糖样沉积症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 3只BMT猫中有3只芳基硫酸酯酶B缺乏。 继骨髓 移植，许多临床特征与过量的GAG相关 储物，例如角膜混浊、面部畸形、不能行走， 并且在供体来源后，GAG的过量尿排泄已经逆转， 具有ASB活性的白细胞已植入。 我们建议扩大 通过进行额外的同种异体骨髓 MPS VI中的移植影响了猫，以确定BMT 可预防、稳定或逆转MPS VI的表现， 骨髓移植时受MPS影响个体的年龄在影响 这种治疗的效果。 我们将在3组5 MPS中进行BMT 分别在12周龄、6个月龄和1岁龄时的VI感染猫， 监测猫BMT前后的以下参数：X线摄影 超声心动图和生物显微镜检查，以评价GAG的作用 在骨骼、心脏、角膜和其他内脏组织中蓄积;以及 光学和电子显微镜积累，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活性以确定是否 植入已经发生，并且酶活性细胞 将逆转GAC在受影响靶组织中的积聚和损伤。 5只未接受BMT治疗的MPS VI受累猫将用作对照。 我们 还建议确定MPS VI对同种异体骨的影响 骨髓移植到未受影响的正常受者，以确定 骨髓来源的细胞负责 糖胺聚糖在各种组织和器官中降解。 结果 这些研究将提供与治疗直接相关的信息， 通过骨髓移植治疗人类溶酶体贮积症。

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.