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。大脑产生保护黑质-纹状体束的多巴胺能神经元的内源性神经营养素。然而，神经营养因子，像其他大分子神经治疗剂一样，在体内不穿过血脑屏障（BBB）。过去尝试将神经营养因子递送到患有PD的人的大脑中已经采用了脑室内（ICV）输注和对流增强扩散（CED）。这两种方法都涉及在神经外科手术后局部经颅递送到大脑，并且这两种方法都已被制药业放弃。另一种策略是重新配制神经营养蛋白治疗剂以使其能够转运穿过BBB，使得神经营养蛋白可以通过外周施用如皮下或静脉内注射来施用。这项研究将产生一种新的重组融合蛋白，其中人类神经营养因子融合到基因工程单克隆抗体（MAb）。MAb通过内源性BBB受体上的受体介导的转运（RMT）穿过BBB。单克隆抗体作为一个分子特洛伊木马（MTH），并渡轮通过血脑屏障所附的神经营养因子。然后，神经营养因子能够激活BBB后面的脑中的神经元神经营养因子受体。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，对各自的靶受体，即BBB受体和神经元受体保持高生物活性。本研究计划的目标是首先在永久转染的宿主细胞中表达MAb-神经营养因子融合基因，然后纯化融合蛋白，以使成年灵长类动物的体内药代动力学和脑摄取测量成为可能。融合蛋白的双功能性随后将用测试与BBB受体和神经元受体两者的结合的测定来验证。公共卫生相关性：帕金森病（PD）影响着美国100万人，是一种严重的脑部退化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丢失引起的。大脑产生一种蛋白质，称为神经营养素，其结果是保护纹状体。然而，由于神经营养因子不能穿过血脑屏障（BBB），因此不能开发PD的神经营养因子药物治疗。目前的研究将使用基因工程开发一种可以穿过BBB的PD特异性神经营养因子。这项研究将导致一种新的神经营养素治疗PD，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.