P-GLYCOPROTEIN MEDIATED CHEMORESISTANCE IN ALS THERAPY

ALS 治疗中 P-糖蛋白介导的化疗耐药

• 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
• 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

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、多特异性和高转运效力使得 P-糖蛋白成为大脑和血脑屏障的选择性看门人，因此成为中枢神经系统药物递送的主要障碍。因此，P-糖蛋白限制了大量药物和异生物质进入中枢神经系统，导致中枢神经系统候选药物的成功率较低，并且可能导致患者对中枢神经系统药物治疗反应的差异。因此，调节 P-糖蛋白可以改善药物输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消除 P-gp 的作用，我们将评估去甲二氢愈创木酸 (NDGA) 对 ALS SOD1-G93A 转基因小鼠模型的治疗效果。我们在基于细胞的 ALS 筛选中确定 NDGA 是一种有效且特异性的谷氨酸转运活性增强剂； SOD1-G93A 小鼠的临床测试表明，其潜在的治疗效果可能受到疾病驱动的脊髓中 P-gp 转运蛋白上调的阻碍。为了进一步评估 NDGA 作为候选治疗剂，我们在目标 1 中建议确定 P-糖蛋白介导的药物耐药性的基因去除是否会在 ALS 小鼠模型中挽救 NDGA 介导的谷氨酸摄取增强作用和治疗效果。在目标 2 中，我们将确定用 NDGA 和 elacridar（一种有效的选择性 P-gp 抑制剂）共同治疗 ALS 小鼠是否会对小鼠产生治疗益处。如果成功，这些方法不仅将确定增加 ALS 小鼠谷氨酸清除率对 ALS 表型的真正影响，而且还将为重新考虑在 ALS 的 SOD1-G93A 小鼠模型中尝试的许多不成功的临床试验提供依据。多药转运蛋白的功能可能会损害可能的积极结果。 公众健康相关性：肌萎缩侧索硬化症 (ALS) 是最具破坏性和致命性的进行性神经肌肉疾病之一。美国有超过 30,000 人患有 ALS，今年将有大约 5,000 名美国人被诊断出患有 ALS。 P-糖蛋白限制了大量药物进入大脑和脊髓，导致候选药物的成功率较低。因此，调节 P-糖蛋白可以改善药物向大脑和脊髓的输送。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-糖蛋白的作用，我们将评估有效的谷氨酸转运增强剂药物 NDGA 对 ALS 小鼠模型的治疗价值。如果成功，这种方法不仅将确定增加 ALS 小鼠谷氨酸清除率的真正治疗影响，而且将为 ALS 开辟新的治疗场所，并为重新考虑在 ALS 小鼠模型中尝试的许多不成功的临床试验提供依据。 P-gp 的功能可能会阻碍可能的积极结果。