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: 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
• 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

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，目前没有有效的治疗方法。的目标 该建议是为了确定有希望的新化合物的潜在有效性和作用机制， OKN-007，我们最近发现它在衰老的运动神经元中具有神经保护作用， ALS突变小鼠模型的初步研究。我们最近对衰老和肌肉减少症的研究使我们 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的损失 破坏，从而改善衰老中的肌肉结果。为此，我们有令人振奋的初步数据 使用OKN-007，小分子，减少老年小鼠运动神经元的损失。OKN-007是硝酮 PBN（α-苯基-N-叔丁基-硝酮）的衍生物，这是一种自旋陷阱，以前已被证明具有有益的 对癌症和其他疾病的影响。硝酮化合物具有已知的抗氧化和抗炎作用， OKN-007在创伤性脑损伤、局灶性缺血/中风和脑缺血/中风中具有神经保护作用。 听力损失我们在衰老小鼠中令人兴奋的初步数据表明，OKN-007可以减少运动神经元的损失， 减少后肢肌肉的去神经支配和减少老年小鼠腓肠肌质量的损失。这些 研究结果使我们假设OKN-007也可能减少运动神经元死亡和延缓疾病 ALS的进展。事实上，我们对初步数据感到鼓舞，这些数据显示， G93 A ALS小鼠模型中脊髓神经元数量和疾病进展延迟 用OKN-007治疗。该试点项目的目标是确认这些初步发现，并测试我们的 假设OKN-007可以保护ALS中的运动神经元损失并延缓疾病进展。在 目的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， ALS的G93 A突变小鼠模型中的疾病进展和存活率。对照组和G93 A小鼠组 将在30日龄、发病时（95天）或3岁时开始用OKN-007在饮用水中治疗 发病后115天（115天），以确定治疗的预防和治疗效果。小鼠将 称重并从60日龄开始评估疾病评分和进展。利用脊髓从 对照组和G93 A小鼠，我们将测量运动神经元数量、炎症标志物、氧化损伤和 细胞死亡的激活，ALS中疾病进展的已知改变。小鼠将在145天处死。 年龄，疾病结束阶段之前。为了评估已知的ALS介导的肌肉表型，我们将测量握力， 从60日龄开始测量强度，在145日龄时测量NMJ形态和神经支配状态， 以及骨骼肌中去神经支配和肌肉萎缩的标志物。将建立小鼠的平行队列， 一旦我们确定了最有效的剂量，就可以测量药物治疗后的存活率。在目标2中，我们将 通过测量OKN-007在运动神经元维持和存活中潜在作用机制 OKN-007对小鼠脊髓运动神经元中基因表达的影响， 目标1.这些研究将为OKN-007的作用机制提供重要信息，并有助于 确定OKN-007是否可能是维持ALS运动神经元健康治疗的良好候选药物 患者