Development and validation of therapy for mucopolysaccharidosis III

 描述(申请人提供)：Sanfilippo综合征粘多糖病III型；MPS III)是一种破坏性的儿童期神经退行性溶酶体储存障碍，目前尚无治愈或有效治疗方法。MPS III的根本原因是分解硫酸乙酰肝素(HS)所需的4种酶中的一种遗传突变，HS是一种在大脑和其他地方发挥重要结构和功能作用的糖胺多聚糖。每种类型的MPS III(A到D)都是由于HS分解途径中的一种不同的酶缺乏所致。我们现在建议开发一种酶替代疗法(ERT)来治疗MPS III，它将改善或逆转由这种疾病引起的灾难性和致命的神经功能下降。由于MPS III的症状主要局限于大脑，因此任何有效的MPS III治疗都必须进入大脑。因此，我们的策略建议将重组人α-N-乙酰氨基葡萄糖-6-硫酸酯酶(RhGNS)鞘内注射(进入脊髓液)，以有效治疗主导MPS III病理的神经症状的根本原因。第一阶段的开发达到或超过了所有里程碑。在这个第二阶段的方案中，我们将使用一种新的MPS III小鼠模型进行体内原理验证研究，并进行可扩展生产和纯化重组人GNS的工艺开发，用于临床前和临床开发。在成功完成这一第二阶段提案后，我们的治疗将为IND前研究做好准备。

 DESCRIPTION (provided by applicant): Sanfilippo syndrome mucopolysaccharidosis type III; MPS III) is a devastating neurodegenerative lysosomal storage disorder of childhood for which there is presently no cure or effective treatment available. The fundamental cause of MPS III is an inherited mutation in one of the 4 enzymes required to catabolize heparan sulfate (HS), a glycosaminoglycan which plays important structural and functional roles in the brain and elsewhere. Each type of MPS III (A through D) is due to deficiency of a different enzyme in the HS breakdown pathway. We now propose to develop an enzyme replacement treatment (ERT) for MPS III that will ameliorate or reverse the catastrophic and fatal neurologic decline caused by this disease. As the symptoms of MPS III are largely localized to the brain any effective MPS III treatment must therefore gain access to the brain. Therefore, our strategy proposes to deliver recombinant human alpha-N- acetylglucosamine-6-sulfatase (rhGNS) intrathecally (into the spinal fluid) to effectively treat the underlying causes of the neurologic symptoms that dominate MPS III pathology. Phase I development met or exceeded all milestones. In this Phase II proposal, we will perform in vivo proof-of-principle studies using a novel MPS III mouse model and perform process development for scalable production and purification of rhGNS for preclinical and clinical development. Following successful completion of this phase II proposal, our therapy will be ready for pre-IND studies.