Enzyme Replacement Therapy for GM1 Gangliosidosis Lysosomal Rare Disease

GM1 神经节苷脂沉积症溶酶体罕见病的酶替代疗法

基本信息

批准号：
8780226
负责人：
CAROLE L. CRAMER
金额：
$ 22.5万
依托单位：
BIOSTRATEGIES, LC
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8780226
关键词：
Address Affect Age Animals Binding Bio-Base Biodistribution Blood - brain barrier anatomy Brain Carbohydrates Cells Cessation of life Childhood Chimeric Proteins Collaborations Data Defect Development Disease Disease Management Disease model Documentation Dose Drug Delivery Systems Drug Kinetics Effectiveness Endothelial Cells Enzymes Family Fibroblasts Future Galactosidase Ganglioside GM1 Gangliosidosis GM1 Gaucher Disease Genes Genetic Goals Growth Healthcare Systems Hereditary Disease Human Human Genetics Investigational New Drug Application Kinetics L-Iduronidase Lead Lectin Legal patent Length Live Birth Lysosomal Storage Diseases Lysosomes Mannose Marketing Mediating Mucopolysaccharidosis I Mus Neuraxis Neurons Organ Organelles Outcome Pathology Patients Pharmaceutical Preparations Phase Plague Plant Leaves Plant Lectins Plants Polysaccharides Prevalence Process Production Proteins Public Health Rare Diseases Research Research Project Grants Ricin Safety Saint Jude Children&apos s Research Hospital Site Small Business Innovation Research Grant Specificity Structure Symptoms System Technology Testing Therapeutic Tissues Viral base brain cell cell type cost design disease phenotype drug candidate enzyme activity enzyme replacement therapy follow-up glucosylceramidase improved in vivo innovation innovative technologies interest international center meetings neonate neurological pathology new technology novel novel therapeutics patient population phase 1 study plant growth/development preclinical study progressive neurodegeneration public health relevance receptor research and development safety testing scale up success symptom management therapeutic enzyme therapeutic target therapy development trafficking uptake

项目摘要

DESCRIPTION (provided by applicant): The goal of this proposal is to develop an effective enzyme replacement therapy (ERT) for patients suffering from GM1 Gangliosidosis by integrating a novel protein fusion ERT cell delivery strategy under development at BioStrategies LC and by exploiting safety, supply, and cost advantages of new plant-based enzyme therapeutics bio-manufacturing systems. GM1 Gangliosidosis is a rare genetic lysosomal storage disorder affecting less than 200,000 people in the U.S. It is caused by a defect in the gene encoding the enzyme ?-galactosidase and is characterized by progressive degeneration of normal childhood development especially in brain function leading to death at an early age. Current treatment options are limited to management of disease symptoms and development of an effective ERT drug has been hindered by challenges of delivering these drugs to the brain and central nervous system. This research project is a collaboration between BioStrategies LC, a company focused on doing innovative research in lysosomal disease ERT development, and St. Jude Children's Research Hospital, an international center for GM1 Gangliosidosis research. This SBIR is designed to lead to an effective ERT-based treatment for GM1 Gangliosidosis patients, a patient population with desperate need for new therapeutic options. Our novel plant lectin-ERT fusion tissue delivery technology could also lead to a paradigm shift for ERT-based treatment approaches in general by developing alternative cell targeting mechanisms aimed at trans-blood-brain-barrier drug delivery. The FDA approval in 2012 of the first plant-made ERT, Elelyso (glucoceribrocidase), to treat Gaucher lysosomal disease and the continued growth of interest in rare diseases will support the competitive potential of innovative technologies incorporating new ERT delivery options and plant-based bio-production. This Phase I project addresses the following specific questions: 1) Are plants capable of producing bioactive human ? -galactosidase (? -gal)? 2) Can ¿-gal-plant lectin fusions be produced that retain both ? -gal enzyme activity and novel carbohydrate-binding/cell targeting selectivity?, and 3) Are these plant-made fusion proteins delivered to GM1 diseased brain cells and corrective for disease phenotype in cellular and animal GM1 disease models? Success in these aims will demonstrate the feasibility of plant-based bioproduction of bioactive lysosomal ? -galactosidase and BioStrategies LC proposed lectin-fusion ERT protein delivery technology. Future follow-up research in a subsequent Phase II SBIR project will complete product characterization and scaled-up production to support preclinical studies for testing safety and efficacy of this new GM1 ERT drug candidate, prerequisites for an IND, investigational new drug, application to FDA.

描述（由申请人提供）：本提案的目标是通过整合 BioStrategies LC 正在开发的新型蛋白融合 ERT 细胞递送策略，并利用安全性、供应性，为患有 GM1 神经节苷脂沉积症的患者开发一种有效的酶替代疗法 (ERT)。以及新型植物酶疗法生物制造系统的成本优势 GM1 神经节苷脂沉积症是一种罕见的遗传性溶酶体贮积症，影响人数不到 200,000 人。它是由编码 β-半乳糖苷酶的基因缺陷引起的，其特征是正常儿童发育尤其是脑功能的进行性退化，导致早期死亡。目前的治疗选择仅限于疾病管理。将这些药物输送到大脑和中枢神经系统的挑战阻碍了有效 ERT 药物的症状和开发。该研究项目是 BioStrategies LC 之间的合作，BioStrategies LC 是一家专注于溶酶体疾病 ERT 创新研究的公司。该 SBIR 旨在为 GM1 神经节苷脂沉积病患者提供有效的基于 ERT 的治疗，这些患者迫切需要新的治疗方案。凝集素-ERT 融合组织递送技术还可以通过开发旨在跨血脑屏障药物递送的替代细胞靶向机制，从而导致基于 ERT 的治疗方法的范式转变。 2012 年，第一个植物制造的 ERT Elelyso（葡萄糖脑苷脂酶）用于治疗戈谢溶酶体病，人们对罕见疾病的兴趣持续增长，这将支持结合新的 ERT 递送选项和植物生物生产的创新技术的竞争潜力。第一阶段项目解决了以下具体问题：1) 植物是否能够产生具有生物活性的人类半乳糖苷酶 (? -gal)？ - 产生的半乳糖-植物凝集素融合物保留了？ -半乳糖酶活性和新颖的碳水化合物结合/细胞靶向选择性？以及 3）这些植物制造的融合蛋白是否被递送至 GM1 患病脑细胞并纠正细胞中的疾病表型和动物 GM1 疾病模型？这些目标的成功将证明基于植物的生物活性溶酶体生物生产和 BioStrategies LC 提出的凝集素融合 ERT 蛋白递送的可行性后续 II 期 SBIR 项目的后续研究将完成产品表征和规模化生产，以支持测试这种新 GM1 ERT 候选药物的安全性和有效性的临床前研究，这是 IND、研究性新药、应用的先决条件。向 FDA 提交。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Enzyme replacement for GM1-gangliosidosis: Uptake, lysosomal activation, and cellular disease correction using a novel β-galactosidase:RTB lectin fusion.

GM1-神经节苷脂沉积症的酶替代品：使用新型β-半乳糖苷酶：RTB 凝集素融合的摄取、溶酶体激活和细胞疾病校正。

DOI：
发表时间：
2016-02
期刊：
影响因子：
3.8
作者：
Condori, Jose;Acosta, Walter;Ayala, Jorge;Katta, Varun;Flory, Ashley;Martin, Reid;Radin, Jonathan;Cramer, Carole L;Radin, David N
通讯作者：
Radin, David N

High-throughput imaging method for direct assessment of GM1 ganglioside levels in mammalian cells.

用于直接评估哺乳动物细胞中 GM1 神经节苷脂水平的高通量成像方法。