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（由适用提供）：该提案的目的是通过整合生物策略LC开发的新型蛋白质融合ERT细胞输送策略，并利用安全，供应，供应和新型植物性enzyme疗法的新型蛋白质融合细胞提供策略来开发有效的酶替代疗法（ERT），以针对患有GM1神经节病的患者开发有效的酶。 GM1神经节病是一种罕见的遗传性溶酶体储存障碍，影响美国少于20万人，是由编码酶的基因缺陷引起的？ - 半乳糖苷酶？ - 半乳糖苷酶，其特征是正常儿童期发育的促进，尤其是在早期导致死亡的正常儿童发育。当前的治疗选择仅限于疾病症状的治疗，而有效的ERT药物的发展受到将这些药物运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之间的合作，该公司致力于从事溶酶体疾病ERT开发方面的创新研究，而St. Jude Children's Research Hospital是国际GM1神经节病研究中心。该SBIR旨在为GM1神经节病患者提供有效的基于ERT的治疗方法，该患者迫切需要新的治疗选择。我们新颖的植物讲座 - 融合组织输送技术也可能通过开发旨在旨在跨血液 - 脑 - 障碍药物递送的替代细胞靶向机制来导致基于ERT的治疗方法的范式转移。 FDA在2012年获得第一批植物性ERT Ellyso（Glucoceribocidase）的批准，用于治疗Gaucher溶酶体疾病，并持续增长对稀有疾病的兴趣，将支持编码新ERT ERT递送期权和基于植物的生物生产的创新技术的竞争潜力。该阶段I项目解决了以下特定问题：1）植物是否能够产生生物活性人类？ - 乳糖苷酶（？ - gal）？ 2） - 可以生产两者都保留两者的 - 植物植物的讲线融合吗？ -GAL酶活性和新型的碳水化合物结合/细胞靶向选择性吗？和3）这些植物性融合蛋白是否递送到GM1分离的脑细胞上并在细胞和动物GM1疾病模型中纠正疾病表型？这些目标的成功将证明生物活性溶酶体的植物性生物生产的可行性？ - 半乳糖苷酶和生物特工LC提出的讲道融合ERT蛋白递送技术。随后的II阶段SBIR项目的未来后续研究将完成产品表征和扩大生产，以支持临床前研究，以测试该新的GM1 ERT候选药物的安全性和效率，这是IND，研究新药的先决条件，对FDA的应用。