Selective CB2 Cannabinoid Agonists as Candidate Therapeutics for ALS

描述(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，其特征是进行性运动神经元丢失、瘫痪和在确诊后2至5年内死亡。目前，还没有有效的药理学药物来治疗这种毁灭性的疾病。肌萎缩侧索硬化症时，神经炎症可能对运动神经元丢失的进展有很大影响。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条件的进展。在G93A-SOD1(G93A)突变小鼠中，我们证明了G93A小鼠脊髓中CB2(而不是CB1)受体的mRNA、受体结合和功能在G93A小鼠脊髓中显著和选择性上调，其时间模式与疾病进展密切相关。更重要的是，两种结构不同的选择性CB2激动剂(AM-1241和L-759,633)在症状出现时开始每日注射，显著维持运动功能，并延长疾病发生后的生存间隔。因此，我们认为选择性CB2激动剂可能代表了ALS的一种新的治疗方式。虽然CB2激动剂可能被证明对这种毁灭性的神经退行性疾病有用，但它们作为药物的发展从根本上受到了它们在水中或其他生物相容载体中的相对不溶性的阻碍。事实上，有几条证据表明，AM-1241的实际最大功效可能被低估了，因为我们初步研究中使用的载体的药物输送不够理想。因此，我们建议需要进行药代动力学研究，以确定在G93A小鼠身上产生AM-1241最大疗效所需的最有效的载体、给药途径和/或剂量。本R21应用程序的当前A1修订版将通过执行以下两个特定目标来“确定ALS的候选疗法”和“获得关于候选疗法有效性的初步数据”：特定目标1将通过筛选John W.Huffman博士(加州大学克莱姆森大学)提供的一系列能够减缓疾病进展和延长G93A小鼠生存的吲哚类和经典大麻类CB2激动剂来确定新型CB2激动剂作为ALS候选疗法。特定目标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模型中已被证明有效。这将通过使用药代动力学研究证明的给药载体和给药路线来实现，以产生最大限度地将AM-1241输送到血清和脊髓。本项目确定的选择性CB2激动剂可能是治疗ALS的第一批有效药物。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对ALS患者的临床试验。项目简介：肌萎缩侧索硬化症(ALS)是一种神经退行性疾病，其特征是进行性运动神经元丢失、瘫痪和在确诊后2至5年内死亡。目前，还没有有效的药物来治疗这种毁灭性的疾病。基于一些令人兴奋的初步证据，该项目将寻求发现被称为“CB2激动剂”的新药，这可能是延长ALS患者生命的第一类有效药物。

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.