Testing OKN-007 as a potential intervention for ALS

测试 OKN-007 作为 ALS 的潜在干预措施

基本信息

批准号：
10259079
负责人：
HOLLY VAN REMMEN
金额：
--
依托单位：
OKLAHOMA CITY VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-10-01 至 2023-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10259079
关键词：
ALS patients Address Affect Age Aging Amyotrophic Lateral Sclerosis Anti-Inflammatory Agents Antioxidants Astrocytes Atrophic Brain Cell Death Clinic Clinical Trials Cochlea Data Denervation Disease Disease Progression Distal Dose Effectiveness Event Gastrocnemius Muscle Gene Expression Generations Glioblastoma Goals Hair Cells Hand Strength Health Hindlimb Human Intervention Ischemia Laboratories Maintenance Malignant Neoplasms Measures Mediating Microglia Morphology Motor Neurons Mus Muscle Muscle function Muscular Atrophy Neuromuscular Diseases Neuromuscular Junction Neurons Onset of illness Outcome Pathology Pathway interactions Patients Pharmaceutical Preparations Pharmacotherapy Phase II Clinical Trials Phenotype Pilot Projects Preventive Preventive measure Property Reactive Oxygen Species Skeletal Muscle Spin Trapping Spinal Cord Stroke Testing Therapeutic Effect Traumatic Brain Injury Work age related amyotrophic lateral sclerosis therapy axonopathy cohort drinking water effective therapy effectiveness testing end stage disease hearing impairment improved in vivo inflammatory marker interest military veteran mitochondrial dysfunction mouse model muscle form mutant mouse model nerve supply neuromuscular neuron loss neuroprotection nitrone oxidative damage preservation response sarcopenia skeletal muscle wasting small molecule transcriptome sequencing treatment effect

项目摘要

Amyotrophic lateral sclerosis (ALS) is a debilitating disease with currently no effective treatments. The goal of this proposal is to define the potential effectiveness of and mechanism of action of a promising new compound, OKN-007, that we have recently found to have neuroprotective effects in motor neurons in aging and in preliminary studies in an ALS mutant mouse model. Our recent studies in aging and sarcopenia have led us to focus on interventions targeted to preserving motor neuron health to reduce loss of innervation and NMJ disruption and therefore improve muscle outcomes in aging. To this end, we have exciting preliminary data using OKN-007, small molecule that reduces loss of motor neurons in aging mice. OKN-007 is a nitrone derivative of PBN (α-phenyl-N-tert-butyl-nitrone), a spin trap that has previously been shown to have beneficial effects in cancer and other pathologies. Nitrone compounds have known antioxidant and anti-inflammatory properties, and OKN-007 has neuroprotective effects in traumatic brain injury, in focal ischemia/stroke and in hearing loss. Our exciting preliminary data in aging mice show that OKN-007 can reduce motor neuron loss, reduce denervation in hindlimb muscle and reduce loss of gastrocnemius muscle mass in older mice. These findings led us to hypothesize that OKN-007 may also reduce motor neuron death and delay disease progression in ALS. Indeed, we are encouraged by our preliminary data that show a preservation of motor neuron number in the spinal cord and a delay in disease progression in the G93A ALS mouse model treated with OKN-007. The goal of this pilot project is to confirm these preliminary findings and test our hypothesis that OKN-007 can preserve motor neuron loss in ALS and delay disease progression. In Aim 1, we will determine the effect of OKN-007 treatment on motor neuron and skeletal muscle outcomes in disease progression and survival in the G93A mutant mouse model of ALS. Cohorts of control and G93A mice will be treated with OKN-007 in drinking water beginning at 30 days of age, at disease onset (95 days), or at 3 weeks post-onset (115 days) to determine preventative and therapeutic effects of the treatment. Mice will weighed and evaluated for disease score and progression beginning at 60 days of age. Using spinal cord from control and G93A mice, we will measure motor neuron number, inflammatory markers, oxidative damage and activation of cell death, known alterations in disease progression in ALS. Mice will be sacrificed at 145 days of age, prior to disease end stage. To assess known ALS mediated muscle phenotypes, we will measure grip strength starting 60 days of age and NMJ morphology and innervation status will be measured at 145 days, as well as markers of denervation in skeletal muscle and muscle atrophy. Parallel cohorts of mice will be set up to measure survival in response to drug treatment once we determine the most effective dose. In Aim 2, we will identify potential mechanisms of action for OKN-007 in motor neuron maintenance and survival by measuring the effect of OKN-007 on gene expression using RNA seq analysis in spinal cord motor neurons from mice in Aim 1. These studies will provide important information on the mechanism of action of OKN-007 and help to establish whether OKN-007 may be a good candidate for treatment to maintain motor neuron health in ALS patients.

肌萎缩侧索硬化症（ALS）是一种使人衰弱的疾病，目前尚无有效的治疗方法。该提案旨在定义一种有前途的新化合物的潜在有效性和作用机制， OKN-007，我们最近发现它对衰老和衰老过程中的运动神经元具有神经保护作用我们最近对 ALS 突变小鼠模型的初步研究使我们得出结论。重点关注旨在保护运动神经元健康的干预措施，以减少神经支配和 NMJ 的丧失为此，我们获得了令人兴奋的初步数据。使用 OKN-007，减少衰老小鼠运动神经元损失的小分子 OKN-007 是一种硝酮。 PBN（α-苯基-N-叔丁基硝酮）的衍生物，一种自旋陷阱，之前已被证明具有有益的作用硝酮化合物具有抗氧化和抗炎作用。 OKN-007 对创伤性脑损伤、局灶性缺血/中风和我们对衰老小鼠的令人兴奋的初步数据表明，OKN-007 可以减少运动神经元损失，减少老年小鼠后肢肌肉的去神经支配并减少腓肠肌质量的损失。研究结果使我们认为 OKN-007 还可能减少运动神经元死亡并延缓疾病事实上，我们的初步数据显示运动能力得到了保留，这让我们感到鼓舞。 G93A ALS 小鼠模型中脊髓神经元数量和疾病进展延迟该试点项目的目标是确认这些初步发现并测试我们的结果。假设 OKN-007 可以保留 ALS 中运动神经元的损失并延缓疾病进展。目标 1，我们将确定 OKN-007 治疗对运动神经元和骨骼肌结果的影响对照组和 G93A 小鼠的 G93A 突变小鼠模型中的疾病进展和存活。将在 30 天龄、疾病发作时（95 天）或 3 岁开始在饮用水中使用 OKN-007 进行处理。发病后几周（115 天），以确定治疗的预防和治疗效果。从 60 天开始使用脊髓进行称重并评估疾病评分和进展。对照小鼠和 G93A 小鼠，我们将测量运动神经数量、炎症标志物、氧化损伤和细胞死亡的激活，已知 ALS 疾病进展的改变，将在 145 天处死小鼠。为了评估已知的 ALS 介导的肌肉表型，我们将测量握力。力量从 60 天开始测量，NMJ 形态和神经支配状态将在 145 天测量，如下以及骨骼肌去神经支配和肌肉萎缩的标记物将被建立平行的小鼠队列。一旦我们确定了最有效的剂量，我们将在目标 2 中衡量对药物治疗的生存率。通过测量确定 OKN-007 在运动神经元维持和存活中的潜在作用机制使用 RNA seq 分析确定 OKN-007 对小鼠脊髓运动神经元基因表达的影响目标 1. 这些研究将提供有关 OKN-007 作用机制的重要信息，并有助于确定 OKN-007 是否是维持 ALS 运动神经元健康的良好治疗候选者患者。