P-GLYCOPROTEIN MEDIATED CHEMORESISTANCE IN ALS THERAPY

ALS 治疗中 P-糖蛋白介导的化疗耐药

基本信息

批准号：
7760178
负责人：
Davide Trotti
金额：
$ 16.73万
依托单位：
THOMAS JEFFERSON UNIVERSITY
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：
2009-03-01 至 2011-08-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7760178
关键词：
Accounting American Amyotrophic Lateral Sclerosis Animals Axonal Transport Biological Availability Blood - brain barrier anatomy Brain Brain Diseases Carrier Proteins Ceftriaxone Cells Clinical Clinical Trials Creosote Diagnosis Disease Drug Delivery Systems Drug Kinetics Drug Transport Drug resistance Drug usage Enhancers Evaluation Excision FDA approved Failure Gatekeeping Genetic Glutamates Goals Human Impairment In Vitro Inflammatory Investigation Life Measurement Mediating Mitochondria Monitor Motor Neurons Multi-Drug Resistance Mus Mutation NIH Program Announcements Neuromuscular Diseases Nordihydroguaiaretic Acid Onset of illness Outcome Oxidative Stress P-Glycoprotein P-Glycoproteins Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Pharmacotherapy Phenotype Plants Preclinical Testing Process Proteins Research Spinal Cord Superoxide Dismutase Synapses Synaptic Cleft System Testing Therapeutic Time Transgenic Mice Treatment Efficacy United States Up-Regulation Xenobiotics animal model development base candidate identification drug candidate excitotoxicity illness length improved in vivo indexing inhibitor/antagonist meetings motor neuron degeneration mouse model multi drug transporter mutant neuroinflammation novel therapeutics overexpression programs protein aggregate public health relevance research clinical testing response success therapy development treatment duration uptake

项目摘要

DESCRIPTION (provided by applicant): High expression levels, multispecificity, and high transport potency makes the P-glycoprotein a selective gatekeeper of the brain and blood-brain barrier and thus a primary obstacle to drug delivery in the CNS. As such, P-glycoprotein limits CNS entry of a large number of drugs and xenobiotics, contributes to the poor success rate of CNS drug candidates, and probably contributes to patient-to-patient variability in response to CNS pharmacotherapy. Modulating P-glycoprotein could therefore improve drug delivery into the CNS and drug therapy. Here, we propose to validate this concept in the context of ALS therapy. By following both genetic and pharmacologic approaches to obliterate the action of P-gp we will evaluate the therapeutic efficacy of nordihydroguaiaretic acid (NDGA) to the SOD1-G93A transgenic mouse model of ALS. We identified NDGA as a potent and specific glutamate transport activity enhancer in a cell-based screen for ALS; clinical testing in the SOD1-G93A mice indicated that its potential therapeutic efficacy could have been hampered by a disease-driven upregulation of P-gp transporters in the spinal cord. To further evaluate NDGA as candidate therapeutic we propose in Aim 1 to determine if genetic removal of P- glycoprotein-mediated pharmacoresistance will rescue NDGA-mediated glutamate uptake enhancing effect and therapeutic efficacy in a mouse model of ALS. In Aim 2 we will determine if co-treatment of the ALS mice with NDGA and elacridar, a potent and selective inhibitor of P-gp, will therapeutically benefit the mice. If successful, these approaches not only will determine the true impact on the ALS phenotype of increasing glutamate clearance in ALS mice, but will also provide the rationale to reconsider many unsuccessful clinical trials that have been attempted in the SOD1-G93A mouse model of ALS in which the function of multidrug transporter proteins could have compromised a possible positive outcome. PUBLIC HEALTH RELEVANCE: Amyotrophic lateral sclerosis (ALS) is one of the most devastating and lethal progressive neuromuscular disorders. Over 30,000 people are living with ALS in the United States and approximately 5,000 Americans will be diagnosed with ALS this year. P-glycoprotein limits the entry into the brain and spinal cord for a large number of drugs and contributes to the poor success rate of drug candidates. Modulating P-glycoprotein could therefore improve drug delivery into the brain and spinal cord. Here, we propose to validate this concept in the context of ALS therapy. By following both genetic and pharmacologic approaches to obliterate the action of P-glycoprotein we will evaluate the therapeutic value of a potent glutamate transport enhancer drug, NDGA, to mice model of ALS. If successful, this approach not only will determine the true therapeutic impact of increasing glutamate clearance in ALS mice, but also will open new therapeutic venues for ALS and provide the rationale to reconsider many unsuccessful clinical trials that have been attempted in mice models of ALS in which the function of P-gp could have hampered a possible positive outcome.

描述（由申请人提供）：高表达水平，多特异性和高运输效力使P-糖蛋白成为大脑和血脑屏障的选择性网守，因此是CNS药物输送的主要障碍。因此，P-糖蛋白限制了大量药物和异种生物的中枢神经系统进入，导致CNS候选药物的成功率较差，并且可能有助于对CNS药物治疗的响应，导致患者到患者的变异性。因此，调节P-糖蛋白可以改善药物递送到中枢神经系统和药物治疗。在这里，我们建议在ALS治疗的背景下验证这一概念。通过遵循遗传和药理学方法来消除P-gp的作用，我们将评估北氢糖酸（NDGA）对ALS的SOD1-G93A转基因小鼠模型的治疗功效。我们将NDGA确定为基于细胞的ALS屏幕中的有效和特定的谷氨酸转运活性增强子。 SOD1-G93A小鼠中的临床测试表明，其潜在的治疗功效可能会受到疾病驱动的脊髓中P-GP转运蛋白的上调的阻碍。为了进一步评估NDGA作为候选治疗方法，我们在AIM 1中提出，以确定P-糖蛋白介导的药物耐药的遗传去除是否会挽救NDGA介导的谷氨酸谷氨酸摄取增强效果和ALS小鼠模型中的治疗功效。在AIM 2中，我们将确定ALS小鼠与NDGA和Elacridar（P-gp的有效抑制剂）的共同治疗是否会在治疗上受益于小鼠。如果成功的话，这些方法不仅会决定对ALS小鼠增加谷氨酸清除率的ALS表型的真正影响，而且还将提供理由，以重新考虑在SOD1-G93A小鼠模型中尝试过的许多失败的临床试验，其中可能会构成多种型转运蛋白的功能。公共卫生相关性：肌萎缩性侧索硬化症（ALS）是最具破坏性和致命性的进行性神经肌肉疾病之一。在美国，有30,000多人与ALS住在一起，今年将被诊断出大约5,000名美国人。 P-糖蛋白限制了大量药物进入大脑和脊髓的进入，并导致候选药物的成功率差。因此，调节P-糖蛋白可以改善药物进入大脑和脊髓。在这里，我们建议在ALS治疗的背景下验证这一概念。通过遵循遗传和药理方法来消除p-糖蛋白的作用，我们将评估有效的谷氨酸转运增强剂NDGA对ALS的小鼠模型的治疗价值。如果成功的话，这种方法不仅可以确定ALS小鼠增加谷氨酸清除率的真正治疗影响，而且还将为ALS开放新的治疗场所，并提供理由，以重新考虑许多在P-GP功能的ALS模型中尝试过的许多失败的临床试验，其中P-GP的功能可能会阻碍阳性结果。