Development and in vitro validation of therapy for mucopolysaccharidosis III

粘多糖贮积症 III 疗法的开发和体外验证

• 批准号: 9020728
• 负责人: SEAN EKINS
• 金额: $ 0.15万
• 依托单位: PHOENIX NEST, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-06 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9020728
• 关键词: Acetylglucosamine; Achievement; Adolescent; Affect; Animal Model; Animals; Biochemical; Biomedical Research; Biotechnology; Birth; Blood - brain barrier anatomy; Brain; Buffers; Cells; Cerebrospinal Fluid; Cessation of life; Childhood; Chinese Hamster Ovary Cell; Cognitive; Confocal Microscopy; Data; Dementia; Development; Disease; Dose; Drug Kinetics; Economics; Effectiveness; Emotional; Enzymes; Exhibits; Family; Fibroblasts; Glycosaminoglycans; Heparitin Sulfate; Human; Impaired cognition; In Vitro; Individual; Inherited; Laboratories; Lead; Learning; Life; Los Angeles; Lysosomes; Marketing; Medical center; Methodology; Modeling; Motivation; Motor Skills; Mucopolysaccharidoses; Mucopolysaccharidosis I; Mucopolysaccharidosis III; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurologic; Neurologic Symptoms; Pathologic; Pathology; Pathway interactions; Patients; Pharmacologic Substance; Phase; Physiological; Play; Primates; Problem behavior; Production; Property; Proteins; Radiolabeled; Recombinants; Research Institute; Role; Small Business Technology Transfer Research; Sulfatases; Symptoms; Therapeutic; Time; Toxic effect; Validation; Vegetative States; Walking; bench to bedside; brain cell; disability; effective therapy; enzyme replacement therapy; enzyme therapy; experience; in vivo; neurobehavioral; pre-clinical; public health relevance; radiotracer; response; scale up; social; success; uptake

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.

描述（由申请方提供）：Sanfilippo病（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。我们现在建议开发一种MPS III的酶替代治疗，以改善或逆转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。我们的合作团队包括Patricia Dickson博士和她在哈博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。Dickson博士是粘多糖类药物的专家，在鞘内酶替代疗法的临床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，rhGNS在中国仓鼠卵巢细胞中的稳健表达可以使规模扩大变得可行。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，以确定进一步开发MPS III治疗方法是否可行，并通过经验数据的强度进行论证：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是否可以进入细胞，到达溶酶体，并减少HS积累。我们的长期目标是尽可能快速有效地生产一种有效的MPS III重组酶疗法。在成功实现目标1和2后，将启动拟定的II期项目，该项目将在动物研究中进行疗效、药代动力学和毒性研究。

项目成果

Doing it All - How Families are Reshaping Rare Disease Research.

全力以赴——家庭如何重塑罕见疾病研究。

• DOI: 10.1007/s11095-018-2481-7
• 发表时间: 2018
• 期刊: Pharmaceutical research
• 影响因子: 3.7
• 作者: Ekins,Sean;Perlstein,EthanO
• 通讯作者: Perlstein,EthanO

Incentives for Starting Small Companies Focused on Rare and Neglected Diseases.

• DOI: 10.1007/s11095-015-1841-9
• 发表时间: 2016-04
• 期刊: Pharmaceutical research
• 影响因子: 3.7
• 作者: Ekins S;Wood J
• 通讯作者: Wood J

Neuropathology of murine Sanfilippo D syndrome.

鼠 Sanfilippo D 综合征的神经病理学。

• DOI: 10.1016/j.ymgme.2021.11.010
• 发表时间: 2021
• 期刊: Molecular genetics and metabolism
• 影响因子: 3.8
• 作者: Takahashi,Keigo;Le,StevenQ;Kan,Shih-Hsin;Jansen,MatthewJ;Dickson,PatriciaI;Cooper,JonathanD
• 通讯作者: Cooper,JonathanD