Development and in vitro validation of therapy for mucopolysaccharidosis III

描述(申请人提供)：Sanfilippo病(粘多糖症III型；MPS III)是一种儿童时期破坏性的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针对MPS III的酶替代疗法，该疗法将改善或逆转由这种疾病导致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。我们的合作团队包括帕特里夏·迪克森博士和她在港湾-加州大学洛杉矶分校医学中心洛杉矶生物医学研究所的同事。迪克森博士是粘多糖病方面的专家，在鞘内酶替代疗法的床到床开发方面具有特殊的专业知识。来自迪克森实验室的令人鼓舞的初步数据显示，重组人神经节苷脂在中国仓鼠卵巢细胞中得到了强劲的表达，这可能使放大成为可能。在开发其他MPS疾病治疗方法的先前经验的基础上，结合首次建议MPS III的治疗可能是可行的初始初步数据，我们现在为I期STTR提出两个目标，以确定我们进一步开发MPS III的治疗方法是否可行，并以经验数据的力量为依据：目标1：确定rhGNS是否具有有利于重组酶治疗的特性。目的2：确定重组人神经节苷脂能否进入细胞，到达溶酶体，减少HS的蓄积。我们的长期目标是为MPS III生产一种有效的重组酶疗法，越快越好。在成功实现目标1和2后，将启动拟议的第二阶段项目，该项目将在动物试验中进行疗效、药代动力学和毒性研究。

DESCRIPTION (provided by applicant): Sanfilippo disease (mucopolysaccharidosis type III; MPS III) is a devastating neurodegenerative lysosomal storage disorder of childhood for which there is 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 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. Our collaborative team includes Dr. Patricia Dickson and her colleagues at the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center. Dr. Dickson is an expert in the mucopolysaccharidoses with specific expertise in the bench-to-bedside development of intrathecal enzyme replacement therapy. Encouraging preliminary data from the Dickson lab shows robust expression of rhGNS in Chinese hamster ovary cells that could make scale-up feasible. Building on this prior experience with developing treatments for other MPS diseases combined with initial preliminary data that for the first time suggests a treatment for MPS III might be practical, we now propose two AIMS for this phase I STTR to determine whether further development of our therapeutic approach to MPS III is feasible and justified by the strength of empiric data: Aim 1: Determine whether rhGNS has properties favorable for a recombinant enzyme therapy. Aim 2: Determine whether rhGNS can enter cells, reach lysosomes, and reduce HS accumulation. Our long-term objective is to produce an effective recombinant enzyme therapy for MPS III as rapidly and efficiently as possible. Upon successful achievement of Aims 1 and 2 will initiate proposed a Phase II project which will access the efficacy, pharmacokinetics and toxicity studies in animal studies.