Targeted Neurotrophin Drug Development in Parkinson's Disease

帕金森病靶向神经营养素药物开发

基本信息

批准号：
7480718
负责人：
RUBEN J. BOADO
金额：
$ 10万
依托单位：
ARMAGEN TECHNOLOGIES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2008-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7480718
关键词：
Address Adult Affect Affinity Affinity Chromatography Anions Binding Biological Biological Assay Bioreactors Blood - brain barrier anatomy Blood capillaries Brain Brain region COS Cells Carbohydrates Cations Cell Line Cells Cephalic Cerebrum Chimeric Proteins Chinese Hamster Chinese Hamster Ovary Cell Chromatography Chronic Clinical Trials Cloning Condition Convection Corpus striatum structure DNA DNA Sequence Data Degenerative Disorder Development Diffusion Dihydrofolate Reductase Disease Dose Drug Delivery Systems Drug Formulations Drug Industry Drug Kinetics Electroporation Engineering Enzyme-Linked Immunosorbent Assay Equipment Experimental Models Experimental Parkinsonism Filtration Future Gene Amplification Gene Expression Generations Genes Genetic Genetic Engineering Goals Guanosine Monophosphate Human Hypoxanthine Hypoxanthines Immunoglobulin G Infusion procedures Injection of therapeutic agent Insulin Receptor Intravenous Isoelectric Focusing Laboratories Lead Legal patent Lesion Light Macaca mulatta Mass Spectrum Analysis Measurement Mediating Methods Methotrexate Molecular Sieve Chromatography Monoclonal Antibodies Neomycin resistance gene Nerve Degeneration Nerve Growth Factor Receptors Neurons Neurosurgical Procedures Ovary Parkinson Disease Peripheral Pharmaceutical Preparations Pharmacologic Substance Pharmacology and Toxicology Pharmacotherapy Phase Placement Plasma Plasmids Polyacrylamide Gel Electrophoresis Preparation Primates Process Production Proteins Public Health Reaction Time Recombinant Fusion Proteins Recombinant Proteins Recombinants Research Research Contracts Robotics Rodent Model Running Serum Serum-Free Culture Media Site Sodium Dodecyl Sulfate Solutions Structure System Technology Testing Therapeutic Thymidine Transgenes United States Food and Drug Administration Western Blotting Work antibiotic G 418 base brain cell brain tract capillary cell bank design dopaminergic neuron drug development expression vector fusion gene human INSR protein humanized monoclonal antibodies in vivo intravenous injection milligram molecular trojan horse neuron loss neuroprotection neurotrophic factor novel progressive neurodegeneration receptor receptor binding subcutaneous transcytosis uptake vector

项目摘要

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a severe degenerative condition of the brain that affects 1 million people in the U.S. PD is caused by the progressive neurodegeneration of the nigral-striatal tract in brain. The brain produces endogenous neurotrophins that protect the dopaminergic neurons of the nigral-striatal tract. However, neurotrophins, like other large molecule neurotherapeutics, do not cross the blood-brain barrier (BBB) in vivo. Past attempts to deliver neurotrophins to the brain of people with PD have employed both intra-cerebroventricular (ICV) infusion and convection-enhanced diffusion (CED). Both approaches involve local, trans-cranial delivery to the brain following a neurosurgical procedure, and both approaches have been abandoned by the pharmaceutical industry. An alternative strategy is the re-formulation of the neurotrophin therapeutic to enable transport across the BBB, so that the neurotrophin can be administered by peripheral administration such as subcutaneous or intravenous injections. This research will produce a novel recombinant fusion protein, whereby a human neurotrophin is fused to a genetically engineered monoclonal antibody (MAb). The MAb crosses the BBB via receptor- mediated transport (RMT) on an endogenous BBB receptor. The MAb acts as a molecular Trojan horse (MTH), and ferries across the BBB the attached neurotrophin. The neurotrophin is then able to activate the neuronal neurotrophin receptor in brain behind the BBB. The fusion protein will be engineered so that both parts of the fusion protein, the MAb part, and the neurotrophin part, maintain high biological activity for the respective target receptors, ie, the BBB receptor and the neuronal receptor. The goal of this research plan is to first express the MAb-neurotrophin fusion gene in a permanently transfected host cell, and then purify the fusion protein to enable in vivo pharmacokinetics and brain uptake measurements in the adult primate. The bi-functionality of the fusion protein will then be verified with assays that test both binding to the BBB receptor and the neuronal receptor. PUBLIC HEALTH RELEVANCE: Parkinson's disease (PD) affects 1 million people in the U.S., and is a severe degenerative disease of the brain. The disease is caused by the loss of brain cells in a region of the brain called the striatum. The brain produces a protein, called a neurotrophin, which results in protection of the striatum. However, neurotrophin drug therapy of PD cannot be developed, because the neurotrophins do not cross the blood-brain barrier (BBB). The present research will use genetic engineering to develop a PD-specific neurotrophin that can cross the BBB. This research will lead to a new neurotrophin treatment of PD, which can be administered by intravenous or subcutaneous administration.

描述（由申请人提供）：帕金森病 (PD) 是一种严重的大脑退行性疾病，在美国影响着 100 万人。PD 是由大脑中黑质纹状体束的进行性神经退行性病变引起的。大脑产生内源性神经营养素，保护黑质纹状体束的多巴胺能神经元。然而，神经营养素与其他大分子神经治疗药物一样，在体内不会穿过血脑屏障（BBB）。过去尝试将神经营养因子输送到帕金森病患者的大脑中，同时采用了脑室内 (ICV) 输注和对流增强扩散 (CED) 方法。这两种方法都涉及在神经外科手术后局部经颅输送到大脑，并且这两种方法都已被制药行业放弃。另一种策略是重新配制神经营养蛋白治疗剂，使其能够穿过血脑屏障运输，从而可以通过外周给药（例如皮下或静脉注射）来施用神经营养蛋白。这项研究将产生一种新型重组融合蛋白，将人类神经营养蛋白与基因工程单克隆抗体 (MAb) 融合。 MAb 通过内源性 BBB 受体上的受体介导的转运 (RMT) 穿过 BBB。 MAb 充当分子特洛伊木马 (MTH)，并通过 BBB 运送附着的神经营养素。然后，神经营养蛋白能够激活 BBB 后面大脑中的神经元神经营养蛋白受体。融合蛋白将被工程化，使得融合蛋白的两个部分(MAb部分和神经营养蛋白部分)对于各自的靶受体(即BBB受体和神经元受体)保持高生物活性。该研究计划的目标是首先在永久转染的宿主细胞中表达 MAb-神经营养蛋白融合基因，然后纯化融合蛋白，以便能够在成年灵长类动物中进行体内药代动力学和脑摄取测量。然后，将通过测试与 BBB 受体和神经元受体结合的测定来验证融合蛋白的双功能性。公共健康相关性：帕金森病 (PD) 影响着美国 100 万人，是一种严重的大脑退行性疾病。这种疾病是由大脑纹状体区域的脑细胞损失引起的。大脑产生一种称为神经营养蛋白的蛋白质，它可以保护纹状体。然而，由于神经营养蛋白不能穿过血脑屏障（BBB），因此无法开发出治疗PD的神经营养蛋白药物。目前的研究将利用基因工程开发一种可以穿过血脑屏障的帕金森病特异性神经营养素。这项研究将带来一种新的神经营养蛋白治疗帕金森病的方法，可以通过静脉或皮下给药的方式进行治疗。