Testing OKN-007 as a potential intervention for ALS

测试 OKN-007 作为 ALS 的潜在干预措施

• 批准号: 10513312
• 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
• 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/10513312
• 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; phenyl-N-tert-butylnitrone; preservation; response; sarcopenia; small molecule; transcriptome sequencing; treatment effect

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.

肌萎缩性侧索硬化症（ALS）是一种令人衰弱的疾病，目前尚无有效治疗。目标 该建议是定义承诺新化合物的潜在有效性和作用机理， OKN-007，我们最近发现在衰老和中的运动神经元中具有神经保护作用 ALS突变小鼠模型中的初步研究。我们最近在衰老和肌肉减少症方面的研究使我们得以 专注于针对保留运动神经元健康以减少神经损失和NMJ的干预措施 破坏，从而改善衰老的肌肉结局。为此，我们有令人兴奋的初步数据 使用OKN-007，小分子可以减少衰老小鼠的运动神经元的损失。 OKN-007是硝基 PBN（α-苯基N-丁基丁基硝酸）的衍生物，一种自旋陷阱，以前已证明具有有益的自旋陷阱 对癌症和其他病理的影响。硝酸化合物具有已知的抗氧化剂和抗炎药 特性和OKN-007在局部缺血/中风和中具有神经保护作用 听力损失。我们令人兴奋的老化小鼠初步数据表明，OKN-007可以减少运动神经元损失， 减少后肢肌肉的神经支配，并减少老鼠老鼠的胃肌肿块的损失。这些 调查结果导致我们假设OKN-007也可能减少运动神经元死亡和延迟疾病 ALS的进展。确实，我们的初步数据使我们感到鼓舞，该数据显示了电动机的保存 脊髓中的神经元数和G93A ALS小鼠模型中疾病进展的延迟 用OKN-007处理。该试点项目的目的是确认这些初步发现并测试我们 OKN-007可以保留ALS运动神经元丧失并延迟疾病进展的假设。在 AIM 1，我们将确定OKN-007治疗对运动神经元和骨骼肌结局的影响 ALS的G93A突变小鼠模型中的疾病进展和存活。对照组和G93A小鼠 从30天大开始，疾病发病（95天）或3岁时，将在饮用水中用OKN-007处理饮用水。 发入后几周（115天）确定治疗的预防和治疗作用。老鼠会 从60天龄的时候开始称重并评估疾病评分和进展。使用脊髓 控制和G93A小鼠，我们将测量运动神经元数，炎症标记，氧化损伤和 细胞死亡的激活，ALS疾病进展的已知改变。小鼠将在145天后牺牲 年龄，疾病末期。为了评估已知的ALS介导的肌肉表型，我们将测量握把 从60天大开始的力量，NMJ的形态和神经支配状态将在145天内测量，为 以及骨骼肌和肌肉萎缩中的神经神经的标志。平行的小鼠队列将设置为 一旦我们确定最有效的剂量，请测量对药物治疗的生存。在AIM 2中，我们将 通过测量，确定运动神经元维持和生存中OKN-007的作用机理 OKN-007使用RNA SEQ分析在脊髓运动神经元中的RNA SEQ分析中的影响 目标1。这些研究将提供有关OKN-007作用机理的重要信息，并有助于 确定OKN-007是否可能是维持ALS运动神经元健康的治疗方法 患者。