Selective CB2 Cannabinoid Agonists as Candidate Therapeutics for ALS

选择性 CB2 大麻素激动剂作为 ALS 的候选治疗药物

基本信息

批准号：
7533341
负责人：
Paul L Prather
金额：
$ 18.81万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-15 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7533341
关键词：
AM 1241 Agonist Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Animal Model Anti-Inflammatory Agents Anti-inflammatory Appearance Biochemical Biocompatible Biological Availability CNR1 gene CNR2 gene Cannabinoids Cessation of life Characteristics Class Clinical Trials Compatible Condition Count Daily Data Development Diagnosis Disease Disease Progression Dose Drug Delivery Systems Drug Kinetics Endocannabinoids Funding Opportunities Future GTP-Binding Proteins Goals Half-Life In Vitro Indoles Injection of therapeutic agent Life Ligands Messenger RNA Metabolic Clearance Rate Modality Motor Motor Neurons Multiple Sclerosis Mus Mutant Strains Mice Neurodegenerative Disorders Onset of illness Paralysed Pathologic Patients Pattern Pharmaceutical Preparations Pharmacologic Substance Range Relative (related person)Research Route Screening procedure Series Serum Signal Pathway Solubility Spinal Cord Staging Symptoms Testing Therapeutic Tissues Translating Universities aqueous base day in vivo indole intraperitoneal mouse model neuroinflammation neuron loss novel novel therapeutics receptor binding relating to nervous system research study response subcutaneous

项目摘要

DESCRIPTION (provided by applicant): Project Summary: Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron loss, paralysis and death within 2 to 5 years of diagnosis. Currently, no effective pharmacological agents exist for the treatment of this devastating disease. Neuroinflammation may greatly influence the progression of motor neuron loss during ALS. Cannabinoids produce anti-inflammatory actions via CB1 and CB2 receptors and delay the progression of pathologic conditions characterized by neuroinflammation. In G93A-SOD1 (G93A) mutant mice, the most well-characterized animal model of ALS, we demonstrate that mRNA, receptor binding and function of CB2, but not CB1, receptors are dramatically and selectively upregulated in the spinal cords of G93A mice in a temporal pattern closely paralleling disease progression. More importantly, daily injections of two structurally diverse selective CB2 agonists (AM-1241 and L- 759,633) initiated at symptom onset, markedly maintain motor function and increase the survival interval after disease onset. Therefore, we propose that selective CB2 agonists may represent a novel therapeutic modality for ALS. While CB2 agonists may prove useful for this devastating neurodegenerative disease, their development as pharmaceutical agents has been fundamentally hindered by their relative insolubility in aqueous, or other biocompatible, vehicles. Indeed, several lines of evidence indicate that the actual maximal efficacy of AM-1241 might have been underestimated due to less than optimal drug delivery by the vehicle employed in our preliminary studies. As such, we propose that pharmacokinetic studies are needed to determine the most efficient vehicle, route of administration and/or dose required to produce the maximal efficacy of AM-1241 in G93A mice. The current A1 revision of this R21 application will "identify candidate therapeutics" and "obtain preliminary data on the efficacy of candidate therapeutics" for ALS by conducting the following two Specific Aims: Specific Aim 1 will identify novel CB2 agonists as candidate therapeutics for ALS by screening a series of indole and classic cannabinoid-based CB2 agonists provided by Dr. John W. Huffman (Clemson University, SC) for their ability to slow disease progression and prolong survival of G93A mice. Specific Aim 2 will optimize the therapeutic potential of AM-1241, a CB2 agonist with proven efficacy in the G93A mouse model of ALS. This will be accomplished by employing the vehicle and route of administration demonstrated by pharmacokinetic studies to produce the greatest delivery of AM-1241 to serum and spinal cords. Selective CB2 agonists identified by this project could be the first efficacious drugs for the management of ALS. Most importantly, our long-term goal is to translate results from these studies into a future clinical trial in ALS patients. Project Narrative: Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron loss, paralysis and death within 2 to 5 years of diagnosis. Currently, no effective drugs exist for the treatment of this devastating disease. Based on some exciting preliminary evidence, this project will seek to discover new drugs called "CB2 agonists" that could be the first class of effective drugs to prolong the lives of ALS patients.

描述（由申请人提供）：项目摘要：肌萎缩侧索硬化症（ALS）是一种神经退行性疾病，其特征是诊断后 2 至 5 年内进行性运动神经元丧失、瘫痪和死亡。目前，尚无有效的药物来治疗这种破坏性疾病。神经炎症可能极大地影响 ALS 期间运动神经元损失的进展。大麻素通过 CB1 和 CB2 受体产生抗炎作用，并延缓以神经炎症为特征的病理状况的进展。在 G93A-SOD1 (G93A) 突变小鼠（最充分表征的 ALS 动物模型）中，我们证明 CB2（而非 CB1）受体的 mRNA、受体结合和功能在 G93A 小鼠的脊髓中显着且选择性上调。与疾病进展密切相关的时间模式。更重要的是，在症状出现时开始每日注射两种结构不同的选择性CB2激动剂（AM-1241和L-759,633），可显着维持运动功能并延长疾病发作后的生存期。因此，我们认为选择性 CB2 激动剂可能代表 ALS 的一种新的治疗方式。虽然 CB2 激动剂可能对这种毁灭性的神经退行性疾病有用，但它们作为药剂的发展由于其在水性或其他生物相容性载体中的相对不溶性而从根本上受到阻碍。事实上，多项证据表明，由于我们初步研究中使用的载体未达到最佳药物输送，AM-1241 的实际最大功效可能被低估。因此，我们建议需要进行药代动力学研究，以确定在 G93A 小鼠中产生 AM-1241 最大功效所需的最有效载体、给药途径和/或剂量。该 R21 申请的当前 A1 修订版将通过以下两个具体目标来“确定 ALS 的候选疗法”并“获得候选疗法功效的初步数据”：具体目标 1 将通过以下方式确定新型 CB2 激动剂作为 ALS 的候选疗法：筛选 John W. Huffman 博士（南卡罗来纳州克莱姆森大学）提供的一系列吲哚和经典大麻素 CB2 激动剂，了解其减缓疾病进展和延长生存的能力G93A 小鼠。具体目标 2 将优化 AM-1241 的治疗潜力，AM-1241 是一种 CB2 激动剂，在 G93A 小鼠 ALS 模型中已证明有效。这将通过采用药代动力学研究证明的载体和给药途径来实现，以最大程度地向血清和脊髓输送 AM-1241。该项目确定的选择性 CB2 激动剂可能是第一个治疗 ALS 的有效药物。最重要的是，我们的长期目标是将这些研究的结果转化为未来针对 ALS 患者的临床试验。项目叙述：肌萎缩侧索硬化症 (ALS) 是一种神经退行性疾病，其特征是诊断后 2 至 5 年内进行性运动神经元丧失、瘫痪和死亡。目前，还没有有效的药物可以治疗这种毁灭性的疾病。基于一些令人兴奋的初步证据，该项目将寻求发现称为“CB2激动剂”的新药，这可能是第一类延长 ALS 患者生命的有效药物。