Enzyme replacement therapy for Sanfilippo A lysosomal rare disease

Sanfilippo A 溶酶体罕见病的酶替代疗法

基本信息

批准号：
9108454
负责人：
CAROLE L. CRAMER
金额：
$ 65.94万
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：
2013-06-15 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9108454
关键词：
Active Sites Address Affect Age Animals Behavioral Binding Biochemical Biodistribution Biological Assay Biomanufacturing Birth Blood - brain barrier anatomy Brain Carbohydrates Cells Cessation of life Childhood Chimeric Proteins Clinical Research Clinical Trials Clinical Trials Design Communities Complex Cyclic GMP Data Defect Dementia Development Disease Dose Drug Delivery Systems Drug Kinetics Effectiveness Enzymes Evaluation Family Feasibility Studies Fibroblasts Gaucher Disease Gene Fusion Genes Genetic Goals Health Health system Hereditary Disease Histopathology Human Human Genetics In Vitro Inorganic Sulfates Lead Lectin Liver Lysosomes Mediating Modification Mucopolysaccharidoses Mucopolysaccharidosis III A Mus Mutation Nerve Degeneration Neuraxis Neurologic Neurologic Symptoms Organ Outcome Pathology Patients Pharmaceutical Preparations Phase Pilot Projects Plant Lectins Plants Positioning Attribute Prevalence Production Protocols documentation Puberty Public Health Qualifying Rare Diseases Reporting Research Research Project Grants Safety Secure Serum Small Business Innovation Research Grant Specificity Spleen Sulfatases Technology Therapeutic TimeLine Tissues Toxicology Unspecified or Sulfate Ion Sulfates Visceral base cell type cost design disease phenotype drug candidate drug development drug production effective therapy emerging adult enzyme activity enzyme replacement therapy formylglycine gene product glucosylceramidase in vivo innovation interest learned behavior meetings mouse model novel novel therapeutics patient population pre-clinical preclinical efficacy programs research and development scale up success sugar symptom management uptake

项目摘要

DESCRIPTION (provided by applicant): The goal of this SBIR 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 heparan 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). 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 could lead to a fundamental paradigm shift for ERT-based treatment approaches based on innovative alternate cell targeting mechanisms, and trans-blood-brain-barrier (BBB) drug delivery. The promise of plant-made bio-production to be employed in this project has recently been recognized with the FDA approval of Elelyso, Protalix/Pfizer's plant-made glucocerebrosidase ERT for Gaucher Disease. The potential for a marketable product is high. With the rare disease community showing escalating interest in reducing drug development and production timelines and costs, our new ERT drug technology utilizing plant- based bio-production will be highly attractive and competitive. All Phase I objectives of this SBIR project have been met demonstrating a) the feasibility of using plant- based bio-manufacturing for our complex human gene product and b) the ability of our lectin carriers to mediate delivery of active sulfamidase into human cells and lysosomes leading to MPS-IIIA disease phenotype correction. This Phase II SBIR proposal addresses the following follow-on objectives: 1) To produce bioactive SGSH:lectin fusion drug products at scale and purity to support in vivo mouse model animal trials, 2) To evaluate in vivo enzyme distribution in normal and MPS-IIIA mice, and 3) To assess efficacy in disease correction of our lead drug candidate in the MPS-IIIA mouse model. Success in Phase II will demonstrate the efficacy of our lectin drug candidate to correct in vivo disease phenotype in the mouse model for this disease supporting subsequent preclinical efficacy and toxicology studies required for a successful IND application to FDA to initiate human clinical trials.

描述（由申请人提供）：该 SBIR 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，同时整合新颖的 ERT 递送策略，为 Sanfilippo A 患者开发一种有效的酶替代疗法 (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 200,000 人。由编码乙酰肝素 N-硫酸酯酶 (SGSH) 的基因缺陷引起，其特征是正常儿童发育尤其是脑功能进行性退化，导致早期死亡，目前的治疗方案仅限于症状管理和发育障碍。有效的 ERT 药物一直受到将这些药物输送到大脑和中枢神经系统 (CNS) 的挑战的阻碍。如果成功，该 SBIR 将为 Sanfilippo A 患者提供基于 ERT 的有效治疗，这是一个急需且有限的患者群体。选项。利用 BioStrategies 的新植物凝集素-ERT 融合和递送技术，该技术将在该项目中得到进一步开发，这项研究可能会导致基于创新的替代细胞靶向机制和跨血脑-基于 ERT 的治疗方法发生根本性的转变。最近，FDA 批准了 Protalix/Pfizer 的植物制造的 Elelyso，该项目采用植物制造的生物生产的前景得到了认可。葡萄糖脑苷脂酶 ERT 治疗戈谢病的市场潜力很大，随着罕见病界对缩短药物开发和生产时间和成本的兴趣日益浓厚，我们利用植物生物生产的新 ERT 药物技术将极具吸引力。该 SBIR 项目的所有第一阶段目标均已实现，证明了 a) 使用基于植物的生物制造技术生产我们复杂的人类基因产品的可行性，以及 b) 我们的凝集素载体介导递送的能力。将活性磺酰胺酶引入人体细胞和溶酶体，从而纠正 MPS-IIIA 疾病表型。该 II 期 SBIR 提案解决了以下后续目标：1) 大规模生产生物活性 SGSH：凝集素融合药物产品，以支持体内小鼠。模型动物试验，2) 评估正常小鼠和 MPS-IIIA 小鼠体内酶的分布，以及 3) 评估我们的主要候选药物在 MPS-IIIA 小鼠模型中的疾病纠正功效。 II 期的成功将证明我们的凝集素候选药物能够纠正小鼠模型中该疾病的体内疾病表型，支持后续的临床前疗效和毒理学研究，以便成功向 FDA 申请 IND 并启动人体临床试验。