Iduronidase Replacement Therapy of the Brain in Hurler's Syndrome

Hurler 综合征的大脑艾杜糖苷酶替代疗法

基本信息

批准号：
8101863
负责人：
RUBEN J. BOADO
金额：
$ 97.79万
依托单位：
ARMAGEN TECHNOLOGIES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-15 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8101863
关键词：
Achievement Affect Affinity Chromatography Anions Award Basic Science Binding Bioreactors Blood - brain barrier anatomy Blood Vessels Blood capillaries Brain Brain Diseases Brain Part Businesses Bypass Cations Cephalic Cessation of life Chemistry Chimeric Proteins Chinese Hamster Ovary Cell Chromatography Clinical Trials Consultations Contracts Development Plans Disease Dose Engineering Enzymes Equus caballus Filtration Funding Future Genetic Engineering Grant Growth Guidelines Human Inborn Errors of Metabolism Injection of therapeutic agent Insulin Receptor Investigational Drugs Investigational New Drug Application L-Iduronidase Letters Macaca mulatta Mediating Mental Retardation Molecular Weight Monoclonal Antibodies Mucopolysaccharidosis I Mucopolysaccharidosis I H National Institute of Neurological Disorders and Stroke Nerve Degeneration Neuraxis Neurons Organ Orphan Drugs Patients Perfusion Pharmaceutical Preparations Pharmacology Pharmacology and Toxicology Phase Preparation Process Production Protein Binding Protein Engineering Proteins Protocols documentation Qualifying Recombinant Fusion Proteins Recombinants Replacement Therapy Research Research Contracts Safety Small Business Innovation Research Grant Sterility Structure System Testing Tissues Translational Research Work abstracting brain cell capillary cost cross reactivity dalton design enzyme activity enzyme replacement therapy fusion gene good laboratory practice human INSR protein human tissue in vivo intravenous administration meetings molecular trojan horse nano novel novel strategies novel therapeutics peptide permease preclinical study programs progressive neurodegeneration public health relevance rat Ran 2 protein receptor receptor mediated endocytosis technology development transcytosis

项目摘要

DESCRIPTION (provided by applicant): Abstract There are over 40 lysosomal storage disorders, and most of these diseases affect adversely the central nervous system (CNS). The mainstay of treatment is enzyme replacement therapy (ERT). However, ERT is not effective for the brain, because the enzymes do not cross the brain capillary wall, which forms the blood-brain barrier (BBB) in vivo. Without treatment of the CNS, the young patients are destined to progressive neurodegeneration and death. The limiting factor in the future treatment of these diseases is the transport of the enzyme across the BBB. Bypass of the BBB with direct injection into the brain is not effective, because only a small part of the brain is treated with a trans-cranial delivery system. Conversely, virtually all cells of the brain can be treated with a trans-vascular delivery system that enables the enzyme to cross the BBB following intravenous administration. A new approach to the BBB delivery of large molecules such as enzymes is the molecular Trojan horse technology. A bi-functional fusion protein is produced with genetic engineering, wherein the missing recombinant enzyme is fused to a BBB molecular Trojan horse. The latter is a genetically engineered protein that is able to cross the human BBB by receptor- mediated transcytosis on endogenous BBB peptide transport systems. Pre-clinical studies show that a large enzyme with a molecular weight >100,000 Daltons, can be delivered to brain via transport across the BBB, following attachment to a BBB receptor-specific Trojan horse. The present work will produce a novel fusion gene encoding human iduronidase and a genetically engineered molecular Trojan horse, which will allow the production of the corresponding fusion protein, AGT-181. This new fusion protein will be a new treatment of the brain in Hurler's syndrome. The aims of this work are to manufacture bioreactor-generated AGT-181, perform the GLP pharmacology-toxicology of this new drug, examine the tissue cross reactivity of AGT-181, and to prepare and file an IND to the FDA for the treatment of the brain in Hurler's syndrome. PUBLIC HEALTH RELEVANCE: Project Narrative Lysosomal storage disorders are serious inborn errors of metabolism, and about 75% of the ~40 lysosomal storage disorders affect the brain. The mainstay of treatment is Enzyme Replacement Therapy (ERT). However, ERT is ineffective in the brain, because the enzymes do not cross the blood-brain barrier (BBB). The present work will produce a novel recombinant fusion protein that is able to both (a) bind a human BBB receptor to trigger transport into the brain, and (b) retain high lysosomal enzyme activity. This novel drug, designated AGT-181, will be new treatment for the brain in Hurler's syndrome.

描述（由申请人提供）：摘要有40多个溶酶体储存障碍，其中大多数疾病会影响中枢神经系统（CNS）。治疗的主要是酶替代疗法（ERT）。但是，ERT对大脑无效，因为酶不会越过体内形成血脑屏障（BBB）的脑毛细管壁。未经CNS治疗，年轻患者注定要进行性神经退行性和死亡。这些疾病的未来治疗中的限制因素是酶在整个BBB上的运输。直接注入大脑的BBB旁路无效，因为只有大脑的一小部分是通过跨颅输送系统处理的。相反，几乎所有大脑的细胞都可以通过跨血管递送系统处理，该系统使酶在静脉内给药后能够越过BBB。 BBB传递大分子（例如酶）的一种新方法是分子特洛伊木马技术。双功能融合蛋白是通过基因工程产生的，其中缺失的重组酶融合到BBB分子木马马。后者是一种基因设计的蛋白质，能够通过内源性BBB肽转运系统的受体介导的转胞胞病穿过人BBB。临床前研究表明，在与BBB受体特异性特洛伊木马的附着之后，可以通过跨BBB的运输传递具有分子量> 100,000 dalton的大酶。目前的工作将产生一个编码人类iduronidase和基因工程的分子马匹的新型融合基因，该基因将允许生产相应的融合蛋白AGT-181。这种新的融合蛋白将是对Hurler综合征中大脑的新治疗方法。这项工作的目的是生产生物反应器生成的AGT-181，进行这种新药的GLP药理学反应，检查AGT-181的组织交叉反应性，并为FDA准备并提交FDA，以治疗Hurler综合征中的大脑。公共卫生相关性：项目叙述性溶酶体储存障碍是代谢的严重天生错误，约有40个溶酶体储存障碍会影响大脑。治疗的主要是酶替代疗法（ERT）。但是，ERT在大脑中无效，因为酶不会穿过血脑屏障（BBB）。目前的工作将产生一种新型的重组融合蛋白，能够（a）结合人BBB受体以触发大脑的转运，（b）保留高溶酶体酶活性。这种新型药物（指定为AGT-181）将是Hurler综合征中大脑的新治疗方法。