Iduronidase Replacement Therapy of the Brain in Hurler's Syndrome

Hurler 综合征的大脑艾杜糖醛酸酶替代疗法

基本信息

批准号：
7601792
负责人：
RUBEN J. BOADO
金额：
$ 98.01万
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 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7601792
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）：摘要溶酶体贮积症有 40 多种，其中大多数疾病对中枢神经系统 (CNS) 产生不利影响。主要治疗方法是酶替代疗法（ERT）。然而，ERT 对大脑无效，因为酶不能穿过脑毛细血管壁，而脑毛细血管壁在体内形成血脑屏障 (BBB)。如果不治疗中枢神经系统，年轻患者注定会出现进行性神经退行性病变和死亡。未来治疗这些疾病的限制因素是酶穿过血脑屏障的运输。绕过血脑屏障直接注射到大脑中的方法并不有效，因为只有一小部分大脑接受了经颅给药系统的治疗。相反，几乎所有大脑细胞都可以通过跨血管递送系统进行治疗，该系统使酶能够在静脉注射后穿过血脑屏障。一种通过血脑屏障传递酶等大分子的新方法是分子特洛伊木马技术。通过基因工程产生双功能融合蛋白，其中缺失的重组酶与BBB分子特洛伊木马融合。后者是一种基因工程蛋白，能够通过内源性 BBB 肽转运系统上受体介导的转胞吞作用穿过人类 BBB。临床前研究表明，分子量 >100,000 道尔顿的大酶在附着于 BBB 受体特异性特洛伊木马后，可以通过 BBB 运输输送到大脑。目前的工作将产生一种编码人艾杜糖醛酸酶的新型融合基因和一种基因工程分子特洛伊木马，这将允许产生相应的融合蛋白AGT-181。这种新的融合蛋白将成为治疗赫勒氏综合症大脑的新方法。这项工作的目的是制造生物反应器产生的 AGT-181，对这种新药进行 GLP 药理学毒理学，检查 AGT-181 的组织交叉反应性，并准备并向 FDA 提交用于治疗以下疾病的 IND 申请：赫勒综合症的大脑。公共健康相关性：项目叙述溶酶体贮积症是严重的先天性代谢错误，约 40 种溶酶体贮积症中约 75% 影响大脑。主要治疗方法是酶替代疗法（ERT）。然而，ERT 在大脑中无效，因为酶不能穿过血脑屏障 (BBB)。目前的工作将产生一种新型重组融合蛋白，它能够（a）结合人类 BBB 受体以触发转运到大脑中，并且（b）保留高溶酶体酶活性。这种新药被命名为 AGT-181，将成为治疗 Hurler 综合征大脑的新疗法。