Development and in vitro validation of therapy for mucopolysaccharidosis III

描述（由申请人提供）：三菲利波病（粘多糖病III型；MPS III）是一种破坏性的儿童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的根本原因是分解硫酸肝素（HS）所需的4种酶之一的遗传突变，硫酸肝素是一种糖胺聚糖，在大脑和其他地方起着重要的结构和功能作用。每种类型的MPS III （A至D）是由于HS分解途径中缺乏不同的酶。我们现在建议开发一种酶替代治疗MPS III，以改善或逆转由这种疾病引起的灾难性和致命的神经功能衰退。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，我们建议将重组人α - n -乙酰氨基葡萄糖-6-硫酸酯酶（rhGNS）注入鞘内（脊髓液中），以有效治疗主导MPS III病理的神经系统症状的潜在原因。我们的合作团队包括帕特里夏·迪克森博士和她在加州大学洛杉矶分校港湾医学中心洛杉矶生物医学研究所的同事。Dickson博士是粘多糖的专家，在鞘内酶替代疗法的从实验室到床边的开发方面具有特定的专业知识。来自Dickson实验室的令人鼓舞的初步数据显示，中国仓鼠卵巢细胞中rhGNS的强劲表达可能使扩大规模成为可能。基于先前开发其他MPS疾病治疗方法的经验，结合首次表明MPS III治疗方法可能可行的初步数据，我们现在为该I期STTR提出两个目标，以确定我们对MPS III治疗方法的进一步开发是否可行，并通过经验数据的强度来证明：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rhGNS能否进入细胞，到达溶酶体，减少HS积累。我们的长期目标是尽可能快速有效地为MPS III生产一种有效的重组酶疗法。在成功实现目标1和目标2后，将启动拟议的第二期项目，该项目将在动物研究中进行功效、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.