Development and validation of therapy for mucopolysaccharidosis III

 描述（由申请方提供）：Sanfilippo综合征粘多糖样沉积症III型（MPS III）是一种儿童期破坏性神经退行性溶酶体贮积症，目前尚无治愈或有效治疗方法。MPS III的根本原因是分解代谢硫酸乙酰肝素（HS）所需的4种酶之一的遗传突变，硫酸乙酰肝素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聚糖。每种类型的MPS III（A至D）是由于HS分解途径中不同酶的缺乏。我们现在建议为MPS III开发一种酶替代治疗（ERT），以改善或逆转这种疾病引起的灾难性和致命性神经功能衰退。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-乙酰葡糖胺-6-硫酸酯酶（rhGNS）鞘内（进入脊髓液），以有效治疗主导MPS III病理学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。在该II期提案中，我们将使用新型MPS III小鼠模型进行体内原理验证研究，并进行工艺开发，用于临床前和临床开发的rhGNS的可扩展生产和纯化。在成功完成II期计划后，我们的治疗将准备进行IND前研究。

 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.