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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）：本提案的目标是通过利用植物酶生物生产的安全性、供应和成本优势，同时整合BioStrategies LC正在开发的新型ERT给药策略，为Sanfilippo A患者开发有效的酶替代疗法（ERT）。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20万人，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症状管理，并且有效的ERT药物的开发受到将这些药物递送至大脑和中枢神经系统（CNS）的挑战的阻碍。最近，FDA批准了Elelyso（他苷酶），Protalix/Pfizer用于戈谢病的植物制葡萄糖脑苷脂酶ERT，从而确认了植物制生物生产的前景。如果成功，SBIR将为Sanfilippo A患者提供有效的基于ERT的治疗，这是一个迫切需要和选择有限的患者群体。利用BioStrategies的新植物凝集素-ERT融合和递送技术将在该项目中进一步开发，该研究将导致基于创新的替代细胞靶向机制，粘膜递送和跨血脑屏障（BBB）活性的ERT治疗方法的根本范式转变。市场化产品的潜力非常大。随着最近FDA批准植物制造的Elelyso和行业对罕见疾病目标的兴趣增加，并降低药物开发和生产成本/时间表，这些用于植物生物生产的新技术具有很强的竞争力。与凝集素递送方面无关，植物来源的SGSH将带来优于哺乳动物细胞来源的SGSH ERT的成本和安全性优势。如果满足凝集素介导的ERT递送的承诺，凝集素：SGSH融合将是MSP-IIIA的治疗选择，并且这种药物递送技术可以广泛地开发以靶向具有强CNS参与或经粘膜递送的适应症的其他疾病。该第一阶段项目将解决以下具体问题：a）植物是否能够产生生物活性的人肝素硫酸酯酶（SGSH）？B）能否产生既保留了GSH酶活性又保留了碳水化合物结合选择性的GSH-植物凝集素融合体？和c）这些植物制造的蛋白质是否被递送到体外Sanfilippo A细胞模型中并在体外Sanfilippo A细胞模型中被校正。I期的成功将证明基于植物的生物活性SHSG和凝集素融合ERT与SGSH的生物生产的可行性，并将支持后续的II期研究，以进一步进行产品表征，扩大生产以支持动物试验，在MSP-IIIA小鼠模型中进行体内疾病校正和ERT功效研究，以及评估BBB转胞吞作用和CNS疾病底物清除。