Enzyme Replacement Therapy for Sanfilippo A Lysosomal Rare Disease

Sanfilippo 溶酶体罕见病的酶替代疗法

基本信息

批准号：
8524571
负责人：
CAROLE L. CRAMER
金额：
$ 28.58万
依托单位：
BIOSTRATEGIES, LC
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-15 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8524571
关键词：
Address Affect Age Agrobacterium Animals Binding Birth Blood - brain barrier anatomy Brain Breathing Carbohydrates Cell Line Cell model Cells Central Nervous System Diseases Cessation of life Childhood Chimeric Proteins Codon Nucleotides Cultured Cells Defect Development Disease Documentation Drug Delivery Systems Effectiveness Endothelial Cells Enzymes Family Fibroblasts GAG Gene Gaucher Disease Genes Genetic Genetic Engineering Goals Health system Heparin Hereditary Disease Human Human Genetics In Vitro Industry Kinetics Lead Lectin Legal patent Length Lysosomes Mammalian Cell Mannose Mediating Mucopolysaccharidoses Mucopolysaccharidosis I Mutation Neuraxis Nose Oral Organ Outcome Pathology Patients Peptide Signal Sequences Pharmaceutical Preparations Phase Plague Plant Leaves Plant Lectins Plants Polysaccharides Production Proteins Puberty Public Health Rare Diseases Research Research Project Grants Ricin Route Safety Small Business Innovation Research Grant Speed Structure Sulfatases Surface Syndrome System Technology Testing Therapeutic TimeLine Tissues Treatment Efficacy Variant Viral base cell type cost cost effective design drug development drug production early childhood emerging adult enzyme activity enzyme replacement therapy flexibility glucosylceramidase improved in vivo innovation interest manufacturing scale-up meetings mouse model neurodevelopment neurological pathology new technology novel novel therapeutics patient population phase 1 study phase 2 study plant growth/development preference programs public health relevance research and development research study scale up success symptom management therapy development transcytosis uptake

项目摘要

DESCRIPTION (provided by applicant): The goal of this proposal is to develop an effective enzyme replacement therapy (ERT) for Sanfilippo A patients by exploiting safety, supply, and cost advantages of plant-based enzyme bioproduction while integrating novel ERT delivery strategies being development at BioStrategies LC. Sanfilippo A (MPS-IIIA) 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 heparin N-sulfatase (SGSH) and is characterized by progressive degeneration in normal childhood development especially in brain function leading to death at an early age. Current treatment options are limited to symptom management and development of an effective ERT drug has been hindered by challenges of delivering these drugs to the brain and central nervous system (CNS). The promise of plant-made bioproduction has recently been recognized with the FDA approval of Elelyso (taliglucerase), Protalix/Pfizer's plant-made glucocerebrosidase ERT for Gaucher Disease. If successful, this SBIR will lead to an effective ERT-based treatment for Sanfilippo A patients, a patient population with desperate need and limited options. Utilizing BioStrategies' new plant lectin-ERT fusion and delivery technology to be further developed during this project, this research will lead to a fundamental paradigm shift for ERT-based treatment approaches based on innovative alternate cell targeting mechanisms, mucosal delivery, and trans-blood-brain-barrier (BBB) activity. The potential for a marketable product is very high. With the recent FDA approval of plant-made Elelyso and industry showing elevated interest in rare disease targets and lowering drug development and production cost/timelines, these new technologies for plant-based bioproduction are highly competitive. Independent of the lectin delivery aspects, plant-derived SGSH will bring cost and safety advantages over mammalian cell-derived SGSH ERT. If the promise of lectin- mediated ERT delivery is met, lectin:SGSH fusions would be a treatment of choice for MSP-IIIA and this drug delivery technology could be broadly developed to target other diseases with strong CNS involvement or indications for transmucosal delivery. This Phase I project will address the following specific questions: a) Are plants capable of producing bioactive human heparin sulfatase (SGSH)?, b) Can SGSH - plant lectin fusions be produced that retain both SGSH enzyme activity and carbohydrate binding selectivity?, and c) Are these plant-made proteins delivered to and corrective in in vitro Sanfilippo A cell models. Success in Phase I will demonstrate the feasibility of plant-based bioproduction of bioactive SHSG and the lectin-fusion ERT with SGSH and will support subsequent Phase II studies to further product characterization, scaled-up production to support animal trials, in vivo disease correction and ERT efficacy studies in MSP-IIIA mouse models, and assessment of BBB transcytosis and CNS disease substrate clearance.

描述（由申请人提供）：该提案的目标是通过利用基于植物的酶生物生产的安全性、供应和成本优势，同时整合正在开发的新型 ERT 递送策略，为 Sanfilippo A 患者开发一种有效的酶替代疗法 (ERT)在 BioStrategies LC。 Sanfilippo A (MPS-IIIA) 是一种罕见的遗传性溶酶体贮积症，在美国影响不到 200,000 人。它是由编码肝素 N-硫酸酯酶 (SGSH) 的基因缺陷引起的，其特征是正常儿童期进行性变性尤其是大脑功能的发育，导致早年死亡。目前的治疗选择仅限于症状管理，并且有效的 ERT 药物的开发因将这些药物输送到大脑和中枢神经系统 (CNS) 的挑战而受到阻碍。最近，随着 FDA 批准 Elelyso（taliglucerase），Protalix/辉瑞公司用于治疗戈谢病的植物葡萄糖脑苷脂酶 ERT，植物生物生产的前景得到了认可。如果成功，该 SBIR 将为 Sanfilippo A 患者提供基于 ERT 的有效治疗，该患者群体迫切需要但选择有限。利用 BioStrategies 在该项目期间进一步开发的新型植物凝集素-ERT 融合和递送技术，该研究将导致基于创新的替代细胞靶向机制、粘膜递送和跨血的基于 ERT 的治疗方法发生根本性的转变-脑屏障（BBB）活动。产品的销路潜力非常大。随着最近 FDA 批准植物制造的 Elelyso，业界对罕见疾病靶点表现出了更高的兴趣，并降低了药物开发和生产成本/时间，这些基于植物的生物生产新技术具有很强的竞争力。与凝集素递送方面无关，植物源 SGSH 将比哺乳动物细胞源 SGSH ERT 带来成本和安全性优势。如果凝集素介导的 ERT 递送的承诺得以实现，那么凝集素：SGSH 融合将成为 MSP-IIIA 的治疗选择，并且这种药物递送技术可以广泛开发以针对具有强烈 CNS 参与或有跨粘膜递送适应症的其他疾病。该第一阶段项目将解决以下具体问题：a) 植物是否能够产生具有生物活性的人肝素硫酸酯酶 (SGSH)？ b) 能否生产同时保留 SGSH 酶活性和碳水化合物结合选择性的 SGSH - 植物凝集素融合物？ c) 这些植物制造的蛋白质是否被输送到体外 Sanfilippo A 细胞模型并在其中进行校正。第一阶段的成功将证明生物活性 SHSG 的植物生物生产以及与 SGSH 的凝集素融合 ERT 的可行性，并将支持后续的第二阶段研究，以进一步产品表征、扩大生产以支持动物试验、体内疾病纠正和MSP-IIIA 小鼠模型中的 ERT 功效研究，以及 BBB 转胞吞作用和 CNS 疾病底物清除的评估。