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）：该提案的目的是通过利用安全性，供应和成本优势来开发有效的酶替代疗法（ERT），同时将基于植物的酶生物生产的成本优势整合在一起，同时整合了生物策略LC开发的新型ERT ERT递送策略。 Sanfilippo A（MPS-IIIA）是一种罕见的遗传溶酶体储存障碍，影响美国少于200,000人，是由编码酶肝素N-硫酸酶（SGSH）的基因缺陷引起的，其特征是在正常儿童中发育，尤其是在早期死亡的正常儿童功能中。当前的治疗选择仅限于症状管理和有效的ERT药物的开发，这受到将这些药物交付给大脑和中枢神经系统（CNS）的挑战。植物制造的生物生产的承诺最近通过FDA的批准（taliglucerase），Protalix/Pfizer的植物性葡萄糖脑苷酶ERT用于Gaucher病。如果成功，该SBIR将为Sanfilippo A，迫切需要和选择有限的患者提供有效的基于ERT的治疗方法。在该项目期间，利用BioStrategies的新植物凝集素融合和递送技术将进一步开发，这项研究将导致基于ERT的基于ERT的治疗方法的基本范式转移基于创新的替代细胞靶向机制，粘膜递送和反植物的脑溶液和反植物 - 脑型 - 脑 - 脑 - 脑型水手（BBB（BBB））的活动。可销售产品的潜力很高。随着FDA最近对植物性Elelyso和行业的批准，对罕见疾病靶标的兴趣升高，并降低了药物开发和生产成本/时间表，这些针对植物性生物生物生物生物生物生物生产的新技术具有很高的竞争力。与植物衍生的SGSH无关，与哺乳动物细胞衍生的SGSH ERT相比，植物衍生的SGSH将带来成本和安全优势。如果满足分泌介导的ERT递送的承诺，则凝集素：SGSH融合将是MSP-IIIA的首选治疗方法，并且该药物输送技术可以广泛开发，以针对其他具有强大中枢神经系统参与或透射传递指示的疾病。该阶段I项目将解决以下特定问题：a）植物是否能够生产生物活性人肝素硫酸硫酸酶（SGSH）？，b）SGSH-植物凝集素融合率是否可以保留SGSH酶活性和碳水化合物的选择性，并且Carbohydrate的选择性？ 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.