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Animal testing of RNA aptamers as ALS drug candidate

RNA适体作为ALS候选药物的动物试验

基本信息

批准号：
10646463
负责人：
LI NIU
金额：
$ 40.7万
依托单位：
STATE UNIVERSITY OF NEW YORK AT ALBANY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-15 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10646463
关键词：
ALS patients AMPA Receptors Acids Amyotrophic Lateral Sclerosis Animal Model Animal Testing Behavior Biological Biological Assay Blood - brain barrier anatomy Blood capillaries Body Weight Brain Brain Stem Bypass Cell Death Cell Nucleus Central Nervous System Cessation of life Chemicals Circulation Cytoplasm DNA-Binding Proteins Diffuse Disease Dose Down-Regulation Drug or chemical Tissue Distribution Enzymes Epilepsy Evolution FDA approved Failure Functional disorder Glutamates Goals Half-Life Immunohistochemistry In Vitro Individual Infusion procedures Injections Intestinal Absorption Ion Channel Knockout Mice Label Ligands Liquid substance Mediating Metabolic Clearance Rate Modeling Monitor Motor Neurons Mus Nature Nerve Degeneration Neurodegenerative Disorders Neurosciences Research Onset of illness Outcomes Research Pathology Patients Permeability Pharmaceutical Preparations Property Protein Isoforms RNA RNA Editing Research Resistance Rest Ribonucleases Riluzole Safety Site Spinal Cord Stroke Survival Rate Synaptic Transmission Testing Therapeutic Toxic effect Transgenic Mice Treatment Efficacy Water Whole-Cell Recordings Work amyotrophic lateral sclerosis therapy antagonist aptamer blood-brain barrier penetration design drug candidate drug development drug discovery dsRNA adenosine deaminase early detection biomarkers efficacy evaluation efficacy testing in vivo inhibitor lipophilicity motor disorder mouse model nervous system disorder novel prevent protein TDP-43 receptor receptor function research clinical testing response side effect small molecule small molecule inhibitor sporadic amyotrophic lateral sclerosis therapy development water solubility

项目摘要

Project Summary The goal of this research is to make a class of RNA aptamers that act as AMPA receptor inhibitors, and test the efficacy and safety of these aptamers in a mouse model. These RNA aptamers could become a new, potential drug candidate for treatment of amyotrophic lateral sclerosis (ALS). ALS is a neurodegenerative disorder characterized by the progressive loss of motor neurons in the brain, brainstem and spinal cord. Currently none of ALS drugs effectively alters the disease course. Developing better inhibitors to control the excessive AMPA receptor activity is a promising strategy for the discovery of new and more effective ALS drugs. This is because Ca2+ influx through abnormally expressed, Ca2+- permeable AMPA receptors in motor neurons leads to selective cell death. Riluzole, one of the two FDA- approved ALS drugs, actually has anti-glutamatergic properties. Using an in vitro evolution approach, we have identified a group of 14 potent RNA aptamers targeting AMPA receptors. These aptamers are more potent, highly selective and water soluble, as compared with conventional small-molecule inhibitors. These properties should enable us to use aptamers at the lowest dose possible to achieve therapeutic efficacy by more tightly and selectively blocking AMPA receptor activities in vivo with minimal or even no dose-dependent side effects. The hypothesis to be tested is that a combination of using aptamers as better AMPA receptor antagonists and testing them in the AR2 mouse model will allow us to assess the therapeutic efficacy and safety of our aptamers. The AR2 mouse is a unique animal model where an abnormally Ca2+-permeable AMPA receptor subunit is expressed in motor neurons, causing eventual cell death. Thus, the AR2 mouse model is ideal to test our AMPA receptor aptamers in blocking abnormal AMPA receptor activity. In Aim 1, we propose to make a large quantity for each of the 14 chemically modified aptamers. These aptamers will be pure, stable and biologically functional assayed by whole-cell recording. In Aim 2, we will test each of these 14 aptamers, both individually and in combination, in first in AR2 mice. Aptamers will be administrated through intracerebroventricular injection to bypass the blood- brain barrier. Aptamer-treated and -untreated mice will be compared for changes in TDP-43 immunohistochemistry, behaviors, loss of motor neurons and body weight, and survival rate to assess the efficacy and the safety of the aptamers. The outcome of this research is to identify a set of aptamers that are efficacious, safe, and well tolerated. If successful, this research should lay ground work for clinical testing of some of these aptamers as a potential new ALS therapy.

项目摘要这项研究的目标是制造一类作为AMPA受体抑制剂的RNA适配子，以及在小鼠模型上测试这些适配子的有效性和安全性。这些RNA适配子可能成为一种治疗肌萎缩侧索硬化症(ALS)的新的潜在候选药物。ALS是一种神经退行性疾病的特征是大脑中运动神经元的进行性丧失，脑干和脊髓。目前，没有一种ALS药物能有效地改变病程。发展中更好的抑制剂来控制AMPA受体的过度活性是一种很有希望的发现策略更有效的肌萎缩侧索硬化症新药。这是因为钙离子通过异常表达的钙离子内流。运动神经元上的通透性AMPA受体导致选择性细胞死亡。利鲁唑，FDA- 批准的肌萎缩侧索硬化症药物，实际上具有抗谷氨酸能特性。使用体外进化方法，我们已经确定了一组针对AMPA受体的14个有效的RNA适配子。这些适配子比与传统的小分子抑制剂相比，它具有效力强、选择性高、水溶性好的特点。这些特性应该使我们能够以尽可能低的剂量使用适体来实现治疗在体内更紧密和选择性地阻断AMPA受体活性的疗效剂量依赖性副作用。需要检验的假设是，将适配子作为更好的AMPA受体拮抗剂，并在AR2小鼠模型中测试它们将使我们能够评估我们的适配子的治疗效果和安全性。AR2小鼠是一种独特的动物模型，其中运动神经元异常表达钙离子通透性AMPA受体亚单位，导致最终细胞死亡。因此，AR2小鼠模型是检测我们的AMPA受体适配子阻断异常的理想模型 AMPA受体活性。在目标1中，我们建议对14个化合物中的每一个进行大量的化学生产修饰适配子。这些适配子将是纯净、稳定和具有生物功能的全细胞检测。正在录音。在目标2中，我们将首先单独和组合测试这14个适体在AR2小鼠身上。适配子将通过脑室注射绕过血液- 大脑屏障。将比较适体处理和未处理的小鼠TDP-43的变化免疫组织化学、行为学、运动神经元和体重的丢失以及存活率来评估适体的有效性和安全性。本研究的结果是确定了一组适配子有效、安全、耐受性好的药物。如果成功，这项研究将为临床奠定基础测试其中一些适配子作为一种潜在的ALS新疗法。