Targeted Neurotrophin Drug Development in Parkinson's Disease

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100万人。PD是由大脑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，保护黑纹状体束的多巴胺能神经元。然而，神经营养因子和其他大分子神经治疗药物一样，在体内不能穿过血脑屏障（BBB）。过去将神经营养物质输送到PD患者的大脑的尝试包括脑室内（ICV）输注和对流增强扩散（CED）。这两种方法都涉及神经外科手术后局部经颅向大脑输送，这两种方法都已被制药行业抛弃。另一种策略是重新配制治疗性神经营养因子，使其能够通过血脑屏障运输，这样神经营养因子就可以通过外周给药，如皮下或静脉注射。本研究将产生一种新的重组融合蛋白，将人神经营养因子与基因工程单克隆抗体（MAb）融合。单抗通过内源性血脑屏障受体的受体介导转运（RMT）穿过血脑屏障。MAb就像一个分子特洛伊木马（MTH），通过血脑屏障运送附着的神经营养因子。然后，神经营养因子能够激活脑血脑屏障后面的神经元神经营养因子受体。将对融合蛋白进行工程设计，使融合蛋白的两个部分，单克隆抗体部分和神经营养因子部分，对各自的靶受体（即血脑屏障受体和神经元受体）保持高的生物活性。本研究计划的目标是首先在永久转染的宿主细胞中表达单克隆抗体-神经营养因子融合基因，然后纯化融合蛋白，以便在成年灵长类动物体内进行药代动力学和脑摄取测量。融合蛋白的双功能将通过测试血脑屏障受体和神经元受体的结合来验证。公共卫生相关性：帕金森病（PD）在美国影响着100万人，是一种严重的大脑退行性疾病。这种疾病是由大脑中一个叫做纹状体的区域的脑细胞损失引起的。大脑会产生一种叫做神经营养因子的蛋白质，它可以保护纹状体。然而，由于神经营养因子不能通过血脑屏障（BBB），目前尚不能开发神经营养因子药物治疗帕金森病。目前的研究将利用基因工程来开发一种pd特异性的神经营养蛋白，这种神经营养蛋白可以穿过血脑屏障。这项研究将导致一种新的神经营养药物治疗PD，它可以通过静脉或皮下给药。

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.