Title: Intracerebroventricular sulfamidase delivery to the Brain

项目摘要 MPS IIIA是溶酶体贮积病;一种关键酶磺酰胺酶（SGSH）缺失的疾病， 细胞，导致称为糖胺聚糖的复合糖的毒性积累，主要在中央 神经系统（CNS）。用于治疗相关类型的病症的主要方法涉及替代药物组合物。 通过注射进入循环系统而丢失酶。酶替代疗法解决了许多方面的问题， 但不幸的是，它不能解决CNS疾病的并发症。该提案重点 开发一种新的酶替代疗法及其在MPS IIIA中的应用， 具有严重神经退行性症状的疾病，但由于运输不良，目前的治疗非常有限 穿过血脑屏障我们已经在一种类似的疾病MPSI上测试了我们的方法;这种疾病缺少一个 艾杜糖醛酸酶（IDUA）。使用与胍基新霉素缀合的艾杜糖醛酸酶（IDUA） （GNeo），一种分子转运蛋白，我们表明我们可以将缺失的酶递送到来自MPS的细胞中， I患者，并且鼻内给予少量的结合酶足以 减少大脑中的病理性糖胺聚糖。该补助金的目的是将SGSH与GNeo结合起来 （GNeo-SGSH），并评估直接输送至中枢的酶替代疗法的有效性。 在MPS IIIA小鼠模型中使用脑室内给药对神经系统的影响。剂量依赖 将评估GNeo-SGSH的生物分布以及对生物化学和组织病理学的影响。疗效 并且将在单次给药和2周给药研究中评估安全性。结果将提供临床前 需要的信息，以进行对人类疾病的新治疗。

PROJECT SUMMARY MPS IIIA is lysosomal storage disease; a disease in which a key enzyme, sulfamidase (SGSH) is missing in cells, resulting in the toxic accumulation of complex sugars called glycosaminoglycans, principally in the central nervous system (CNS). A primary approach for treating related types of disorders involves replacement of the missing enzyme by injection into the circulation. Enzyme replacement therapy resolves many aspects of the disease but unfortunately it does not resolve complications of the disease in the CNS. This proposal focuses on the development of a novel way to perform enzyme replacement therapy and its application to MPS IIIA, a disease with severe neurodegenerative symptoms but with very limited current therapies due to poor transport across the blood-brain barrier. We have tested our approach on a similar disease, MPSI; which is missing a different key enzyme called iduronidase (IDUA). Using iduronidase (IDUA) conjugated to guanidinoneomycin (GNeo), a molecular transporter, we showed that we can deliver the missing enzyme to cells derived from MPS I patients and that intranasal administration of small amounts of the conjugated enzyme were sufficient to reduce pathological glycosaminoglycans in the brain. The purpose of this grant is conjugate SGSH with GNeo (GNeo-SGSH) and assess the effectiveness of enzyme replacement therapy delivered directly to the central nervous system in the MPS IIIA mouse model using intracerebroventricular administration. Dose-dependent biodistribution of GNeo-SGSH and effects on biochemical and histological pathology will be evaluated. Efficacy and safety will be assessed in single dose and 2-week dosing studies. The results will provide the preclinical information needed to proceed towards a novel treatment of the disease in humans.