Intranasal Sulfamidase Delivery to the Brain

 描述（由申请方提供）：MPS IIIA（Sanfilippo A）是一种细胞中关键酶缺失导致一种称为糖胺聚糖的复合糖在各种组织中蓄积的疾病。治疗相关类型疾病的主要方法包括通过注射到循环中来替代缺失的酶。酶替代疗法解决了疾病的许多方面。不幸的是，酶替代不能解决中枢神经系统疾病的并发症。该提案的重点是开发一种新的方法来进行酶替代疗法及其应用于MPS IIIA，目前没有治疗选择的疾病。我们表明，我们可以提供失踪的酶从MPS IIIA患者的细胞和静脉注射修饰的酶减少存储的MPS IIIA（Sgsh-/-）的小鼠模型中的糖胺聚糖。此外，经修饰的酶的鼻内给药证明了高水平的递送至脑和病理性糖胺聚糖的减少。该补助金的目的是优化MPS IIIA小鼠模型中酶向中枢神经系统的转移，然后在长期（6个月）研究中评估疗效和安全性。这些结果将为人类疾病的新治疗提供所需的临床前信息。

 DESCRIPTION (provided by applicant): MPS IIIA (Sanfilippo A) is a disease in which a key enzyme is missing in cells resulting in the accumulation of a type of complex sugar called a glycosaminoglycan in various tissues. 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. Unfortunately, enzyme replacement does not resolve complications of the disease in the central nervous system. This proposal focuses on the development of a novel way to perform enzyme replacement therapy and its application to MPS IIIA, a disease with no current therapeutic options. We show that we can deliver the missing enzyme to cells derived from MPS IIIA patients and that intravenous injection of modified enzyme reduces storage of glycosaminoglycans in a mouse model of MPS IIIA (Sgsh-/-). Furthermore, intranasal administration of modified enzyme demonstrated high levels of delivery to the brain and reduction of pathological glycosaminoglycans. The purpose of this grant is to optimize the transfer of enzyme into the central nervous system in the MPS IIIA mouse model and then assess the efficacy and safety in a long-term (6-month) study. The results will provide the preclinical information needed to proceed towards a novel treatment of the disease in humans.