Enzyme Replacement Therapy for GM1 Gangliosidosis Lysosomal Rare Disease

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质融合ERT细胞递送策略，并利用新的植物酶治疗生物制造系统的安全性，供应和成本优势，为GM1神经节脂质病患者开发有效的酶替代疗法（ERT）。GM1神经节脂质沉积症是一种罕见的遗传性溶酶体储存疾病，在美国影响不到20万人。它是由编码这种酶的基因缺陷引起的。-半乳糖苷酶，其特征是正常儿童发育的进行性退化，特别是在导致早期死亡的脑功能方面。目前的治疗选择仅限于疾病症状的管理，有效ERT药物的开发受到将这些药物输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（专注于溶酶体疾病ERT发展的创新研究公司）和St. Jude儿童研究医院（GM1神经节脂质沉积症研究的国际中心）之间的合作。该SBIR旨在为GM1神经节脂质沉积症患者提供有效的基于ert的治疗，这是一个迫切需要新的治疗选择的患者群体。我们的新型植物凝集素- ert融合组织递送技术也可能通过开发针对跨血脑屏障药物递送的替代细胞靶向机制，导致基于ert的治疗方法的范式转变。FDA于2012年批准了首个植物性ERT Elelyso（糖苷化酶）用于治疗戈谢溶酶体病，以及对罕见病兴趣的持续增长，将支持创新技术的竞争潜力，包括新的ERT递送选择和植物性生物生产。本一期项目解决以下具体问题：1)植物是否能够生产具有生物活性的人类？牛乳糖(?加)?2)能否产生既保留两者的植物凝集素融合体？-gal酶活性和新的碳水化合物结合/细胞靶向选择性？3)在细胞和动物GM1疾病模型中，这些植物合成的融合蛋白是否传递到GM1病变脑细胞并纠正疾病表型？这些目标的成功将证明以植物为基础生物生产生物活性溶酶体的可行性。-半乳糖苷酶和BioStrategies LC提出了凝集素融合ERT蛋白递送技术。后续二期SBIR项目的后续研究将完成产品表征和规模化生产，以支持临床前研究，测试这种新的GM1 ERT候选药物的安全性和有效性，这是IND的先决条件，研究性新药，向FDA申请。

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.