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：
8905284
负责人：
CAROLE L. CRAMER
金额：
$ 83.17万
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 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8905284
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 system Hereditary Disease Histopathology Human Human Genetics In Vitro Inorganic Sulfates Lead Lectin Liver Lysosomes Mediating Modification Mucopolysaccharidoses Mus Mutation Nerve Degeneration Neuraxis Neurologic Neurologic Manifestations Organ Outcome Pathology Patients Pharmaceutical Preparations Phase Pilot Projects Plant Lectins Plants Positioning Attribute Prevalence Production Proteins Protocols documentation Puberty Public Health Qualifying Rare Diseases Reporting Research Research Project Grants Safety Secure Serum Small Business Innovation Research Grant Specificity Spleen Sulfatases Syndrome 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 glucosylceramidase in vivo innovation interest learned behavior meetings mouse model novel novel therapeutics patient population pre-clinical preclinical efficacy programs public health relevance 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（由适用提供）：该SBIR提案的目的是通过利用安全性，供应和基于植物的酶生物生产的成本优势来开发有效的酶替代疗法（ERT），同时将新颖的ERT ERT递送策略整合为BioStrategies LC的开发，同时将基于植物的酶生物生产的成本优势。 Sanfilippo A（MPS-IIIA）是一种罕见的遗传性溶酶体储存障碍，影响美国少于20万人，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的脑部功能中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SYM管理，并且将这些药物运送到大脑和中枢神经系统（CNS）的挑战所阻碍了有效的ERT药物的开发。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的新植物讲座融合和输送技术将进一步开发，这项研究可能会导致基于ERT替代性细胞靶向机制和反式脑型脑 - 脑 - 脑障碍（BBB）药物的基于ERT的治疗方法的基本范式转移。通过FDA的批准，Protalix/Protalix/Pfizer的植物性葡萄糖核苷酶ERT用于Gaucher病，该项目将在该项目中进行植物制造的生物生产的承诺。可销售产品的潜力很高。随着稀有疾病界表现出对减少药物开发和生产时间表和成本的兴趣不断提高，我们利用基于植物的生物生产的新ERT药物技术将具有很高的吸引力和竞争力。已经达到了该SBIR项目的所有I阶段目标，证明了a）将基于植物的生物制造用于我们的复杂人类基因产物的可行性，b）我们的演讲携带者介导活性磺胺酶向人类细胞和溶酶体递送的能力，导致MPS-IIIA疾病疾病表型矫正。该II期SBIR提案解决了以下以下目标：1）生产生物活性SGSH：凝集素融合药物的规模和纯度以支持体内小鼠模型动物试验，2）评估在正常和MPS-IIIIA小鼠中的体内酶分布，并评估疾病在我们的MOPS prestiatia the Morps-tragicia中评估疾病的有效性。第二阶段的成功将证明我们的讲座药物在小鼠模型中纠正体内疾病表型的有效性，以支持随后的临床前效率和毒理学研究，成功地将IND应用于FDA启动人类临床试验所需。