Targeted neuromodulation strategies to delay hypoglossal motoneuron death and preserve tongue strength, function, and structure in a mouse model of ALS

延缓 ALS 小鼠模型舌下运动神经元死亡并保持舌头力量、功能和结构的靶向神经调节策略

• 批准号: 10527999
• 负责人: TERESA E LEVER
• 金额: $ 42.7万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10527999
• 关键词: ALS patients; Address; Adverse effects; Age-Months; Amyotrophic Lateral Sclerosis; Atrophic; Axon; Body Weight; Body Weight decreased; Bolus Infusion; Brain Stem; Cessation of life; Clinical; Data; Deglutition; Deglutition Disorders; Early Diagnosis; Early treatment; Eating; Electrodes; Electrophysiology (science); Enteral Feeding; Exercise Therapy; FDA approved; Fatigue; Fluoroscopy; Frequencies; Functional disorder; Growth; Health; Histologic; Hypoglossal nerve structure; Impairment; Injections; Intuition; Isometric Exercise; Life; Longevity; Measures; Mental Depression; Methods; Modeling; Morbidity - disease rate; Motor; Motor Neurons; Mus; Muscle; Muscle Contraction; Nerve; Nervous System Trauma; Neurologic; Neuromuscular Junction; Neuronal Plasticity; Neurons; Onset of illness; Oropharyngeal; Outcome; Paralysed; Pathologic; Penetrance; Pharmaceutical Preparations; Phenotype; Physical Exercise; Placebos; Procedures; Proxy; Quality of life; Resistance; Riluzole; Social isolation; Specificity; Spinal; Structure; Symptoms; Testing; Therapeutic; Therapeutic Effect; Time; Tongue; Training; Transfection; Transgenic Mice; Travel; Work; alternative treatment; axon growth; base; behavior test; cell motility; drinking; end stage disease; exercise training; experimental study; gene therapy; hypoglossal nucleus; implantation; improved; improved outcome; insight; mortality; mortality risk; mouse model; muscle reinnervation; nerve supply; neuronal survival; neurophysiology; neuroregulation; novel; optical fiber; optogenetics; palliative; phenylmethylpyrazolone; preservation; prevent; resistance exercise; response; superoxide dismutase 1; therapeutically effective; tool; translational impact; translational model; translational potential; treatment effect; treatment program; treatment strategy

Project Summary One of the most debilitating consequences of amyotrophic lateral sclerosis (ALS) is swallowing impairment (dysphagia), which is associated with significant morbidity, depression/social isolation, and early mortality. From a neurological perspective, dysphagia in ALS has been attributed to progressive tongue weakness caused by degeneration of brainstem hypoglossal neurons and their axons (hypoglossal nerve) innervating the tongue muscles. Progressive tongue weakness and atrophy ultimately render nearly all ALS patients unable to eat and drink naturally; instead, they must depend on a feeding tube for survival. Despite the multiple life-threatening consequences of dysphagia in ALS, current therapies, including the FDA-approved drugs riluzole and edaravone, have no beneficial effect on swallowing function. Therefore, there is an urgent clinical need to identify effective therapeutic solutions targeting the underlying pathophysiology of dysphagia to preserve swallowing function, and by proxy, significantly extend survival and improve the quality of life for ALS patients. In this project, to address this clinical need, we will leverage a translational mouse model of ALS with dysphagia to explore optogenetic stimulation (opto-stim) as a therapeutic strategy targeting the tongue. The opto-stim treatment is a gene therapy-based approach that has been shown to promote neuronal survival, nerve growth, and muscle reinnervation in nervous system injury. In our approach, we will use opto-stim to selectively “excite” hypoglossal neurons to cause tongue muscle contraction/resistance that mice must overcome to sufficiently protrude the tongue while voluntarily drinking from a waterspout. We hypothesize that this regime, synergistically integrating the benefits of optogenetics and tongue exercise training, has the potential to prevent or slow down the progression of hypoglossal degeneration and associated tongue weakness. To explore the effects of opto-stim treatment, our project is divided into two aims. In Aim 1, we will apply high- and low-frequency opto-stim treatments three times per week in ALS mice, initiated at clinical disease onset (i.e., start of body weight decline), and assess the treatment effect on tongue motility and swallowing function (via fluoroscopy) and lick force (via force-lickometer) from disease onset to end-stage (i.e., 20% weight loss). In Aim 2, we will employ a variety of histological assessments to quantify the corresponding neuroplastic changes in the hypoglossal nucleus neurons, hypoglossal nerve, and the tongue muscles in response to each neuromodulation strategy to establish clinico-pathological correlations. Our results will provide insight into therapeutic effects and mechanisms of optogenetic-based treatment strategies in ALS. Optogenetics has been gaining increasingly significant translational potential and may be particularly beneficial for advanced-stage ALS patients who cannot participate in alternative treatment programs but may still respond to treatment.

项目摘要 肌萎缩性外侧硬化症（ALS）最令人衰弱的后果之一是吞咽障碍 （吞咽困难），这与明显的发病率，抑郁/社会隔离和早期死亡有关。从 ALS中的吞咽困难是一种神经学角度，归因于渐进的舌头无力 脑干降临神经元及其轴突（降压神经）的变性使舌头支配 肌肉。渐进的舌头无力和萎缩最终使几乎所有无法进食的ALS患者 自然喝酒；取而代之的是，它们必须依靠喂食管以生存。尽管威胁生命多种多样 ALS中吞咽困难的后果，包括FDA批准的药物Riluzole和 Edaravone，对吞咽功能没有有益的影响。因此，紧急临床需要识别 针对吞咽困难的潜在病理生理学以保存吞咽的有效治疗溶液 功能，并通过代理，可以显着扩大生存率并改善ALS患者的生活质量。 在该项目中，为了满足这种临床需求，我们将利用ALS翻译的鼠标模型 吞咽困难以探索光遗传刺激（光刺）作为针对舌头的治疗策略。 Opt-stim治疗是一种基于基因治疗的方法，已被证明促进神经元存活，神经 神经系统损伤中的生长和肌肉加剧。在我们的方法中，我们将使用opt-stim选择性地 “激发”降临神经元会引起舌头肌肉收缩/抵抗，必须克服小鼠 在自愿从水面喝酒的同时，足够伸出舌头。我们假设这个制度， 协同结合光遗传学和舌锻炼的好处，有可能防止 或减慢降压变性和相关舌头无力的进展。 为了探索Opt-stim处理的影响，我们的项目分为两个目标。在AIM 1中，我们将申请 在ALS小鼠中每周三次高频和低频Opt-stim治疗，在临床疾病上启动 发作（即体重下降的开始），并评估对舌头运动和吞咽的治疗效果 功能（通过荧光镜检查）和舔力（通过疾病发作到终阶段的力量计）（即重量20％） 损失）。在AIM 2中，我们将采用各种组织学评估来量化相应的神经塑性 降临核核神经元，降临核神经和舌头肌肉的变化响应于每种肌肉 建立临床病理相关性的神经调节策略。我们的结果将提供有关 ALS中基于光遗传学的治疗策略的治疗作用和机制。光遗传学已经存在 具有越来越重要的翻译潜力，可能对先进的ALS特别有益 无法参加替代治疗计划但仍可能对治疗做出反应的患者。