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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，并利用新型植物酶治疗剂生物制造系统的安全性、供应和成本优势，为患有GM 1神经节苷脂沉积症的患者开发有效的酶替代疗法（ERT）。GM 1神经节苷脂沉积症是一种罕见的遗传性溶酶体贮积症，在美国影响不到20万人。这种疾病是半乳糖苷酶引起的，其特征在于正常儿童发育，特别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症状的管理，并且有效的ERT药物的开发受到将这些药物递送到大脑和中枢神经系统的挑战的阻碍。该研究项目是BioStrategies LC（一家专注于溶酶体疾病ERT开发创新研究的公司）和St. Jude Children's Research Hospital（一家GM 1神经节苷脂沉积症研究的国际中心）之间的合作。该SBIR旨在为GM 1神经节苷脂沉积症患者提供有效的基于ERT的治疗，该患者人群迫切需要新的治疗选择。我们的新型植物凝集素-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，为基于ERT的治疗方法带来范式转变。FDA于2012年批准了第一种植物制造的ERT Elelyso（葡萄糖酸苷酶），用于治疗戈谢溶酶体病，以及对罕见疾病的持续增长的兴趣将支持创新技术的竞争潜力，这些技术将新的ERT交付选择和植物生物生产结合在一起。第一阶段的项目解决了以下具体问题：1）植物是否能够产生生物活性的人类？- 半乳糖苷酶（？-gal）？2)可以产生保留两者的半乳糖-植物凝集素融合体吗？-gal酶活性和新型碳水化合物结合/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到GM 1患病的脑细胞并在细胞和动物GM 1疾病模型中校正疾病表型？在这些目标的成功将证明植物为基础的生物生产的生物活性溶酶体的可行性？- 半乳糖苷酶和BioStrategies LC提出的凝集素融合ERT蛋白递送技术。后续II期SBIR项目中的后续研究将完成产品表征和规模化生产，以支持临床前研究，以测试这种新型GM 1 ERT候选药物的安全性和有效性，这是IND、研究性新药和向FDA申请的先决条件。