Superior laryngeal nerve stimulation for the treatment of neurogenic dysphagia in an animal model of amyotrophic lateral sclerosis

优越的喉神经刺激治疗肌萎缩侧索硬化症动物模型中的神经源性吞咽困难

• 批准号: 9405059
• 负责人: Navid Khodaparast
• 金额: $ 4.11万
• 依托单位: NUVIANT MEDICAL INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-23 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9405059
• 关键词: Acute; Admission activity; Adverse effects; Affect; American; Amyotrophic Lateral Sclerosis; Animal Model; Animals; Aspiration Pneumonia; Behavioral; Biological Process; Brain; Brain Stem; Cell Nucleus; Cerebral Palsy; Chin; Chronic; Collaborations; Complex; Cranial Nerves; Deglutition; Deglutition Disorders; Dementia; Development; Diet Modification; Disease; Effectiveness; Electric Stimulation; Enteral Feeding; Epilepsy; Esthesia; Food; Frequencies; Future; Goals; Healthcare; Hospitals; Human; Impairment; Intervention; Investigation; Knowledge; Larynx; Lesion; Life; Liquid substance; Malnutrition; Medical; Methods; Missouri; Morbidity - disease rate; Motor; Mus; Muscular Dystrophies; Nerve Fibers; Nervous system structure; Neurodegenerative Disorders; Neurologic; Neurons; Newly Diagnosed; Oral cavity; Parkinson Disease; Patients; Pattern; Perception; Pharyngeal structure; Phase; Physiology; Protocols documentation; Quality of life; Reflex action; Refractory; Research; Role; Secondary to; Sensory; Shapes; Source; Stimulus; Stomach; Stroke; Structure of superior laryngeal nerve; Taste Perception; Technology; Temperature; Time; Touch sensation; Transgenic Mice; Travel; Universities; Vagus nerve structure; Wakefulness; afferent nerve; aging population; awake; clinical translation; experimental study; innovation; mortality; mouse model; nervous system disorder; neurotransmission; novel; palliative; public health relevance; restorative treatment; sensory input; superoxide dismutase 1; vagus nerve stimulation

 DESCRIPTION (provided by applicant): Dysphagia refers either to the difficulty with the initial phases of a swallow or to the sensation that foods and or liquids are somehow being obstructed in their passage from the mouth to the stomach. As many as 600,000 Americans are newly diagnosed with dysphagia each year, primarily as a result of neurological diseases like amyotrophic lateral sclerosis (ALS), stroke, dementia, Parkinson's disease, muscular dystrophy, and cerebral palsy. Approximately 60-80% of patients with neurodegenerative disease are affected by dysphagia. Dysphagia is highly correlated with malnutrition and aspiration pneumonia, which result in poor quality of life and contributes significantly to increased morbidity and mortality. Current treatments for this debilitating and life-threatening condition ar limited to diet modifications (e.g., thickened liquids), behavioral adaptations (e.g., tucking the chin when swallowing), and other palliative interventions (e.g., feeding tubes) as efforts to extend survival. Despite being a major source of morbidity and mortality for a myriad of neurologic conditions, there are few treatment options for dysphagia. nUro, Inc. ("nUro") - in collaboration with Dr. Teresa Lever (University of Missouri) - is developing implantable neurostimulation technology to provide a new treatment option for patients with dysphagia. The nUro technology targets the superior laryngeal nerve (SLN), which contains predominantly sensory nerve fibers that relay information about temperature, taste, and touch from the larynx and pharynx to the brain. Nerve signals traveling from the SLN to the brain contribute to the orchestration of the triggering, shaping, and timing of the sequential motor pattern of swallowing. We hypothesize that chronic SLN stimulation will selectively facilitate swallowing in patients with neurogenic dysphagia. The broad, long-term objective of this proposed research is to establish SLN stimulation as a novel and effective preventative/restorative treatment for dysphagia in ALS and other chronic neurological conditions that cause dysphagia-associated morbidity and mortality. The immediate goal of the proposed application is to optimize a protocol for chronic SLN stimulation in a mouse model of ALS. In this Phase 1 proposal, we will demonstrate the feasibility of chronic SLN stimulation therapy by investigating the efficacy of this innovative approach to maintain healthy swallowing function in a transgenic mouse model of ALS. By identifying the appropriate treatment parameters in unanesthetized, ambulatory mice (Specific Aim 1) and demonstrating that ALS-affected mice can maintain healthy swallowing function and survive significantly longer as a result of chronic SLN stimulation (Specific Aim 2), we will establish the feasibility necessary to begin investigation and development of a human therapy for dysphagia in ALS. Results will lay the groundwork for using chronic SLN stimulation for long-term management of dysphagia in patients with ALS and other chronic neurological conditions that cause dysphagia-associated morbidity and mortality.

 描述（由申请人提供）：吞咽困难是指吞咽初始阶段的困难，或者是指食物和/或液体在从口腔到胃的通道中受到某种阻碍的感觉。每年有多达60万美国人被新诊断出患有吞咽困难，主要是由于神经系统疾病，如肌萎缩性侧索硬化症（ALS）、中风、痴呆、帕金森病、肌肉萎缩症和脑瘫。大约60-80%的神经退行性疾病患者受到吞咽困难的影响。吞咽困难与营养不良和吸入性肺炎高度相关，导致生活质量差，并显著增加发病率和死亡率。目前对这种使人衰弱和危及生命的病症的治疗仅限于饮食改变（例如，增稠的液体），行为适应（例如，吞咽时收起下巴），以及其它姑息性干预（例如，喂养管）作为延长生存的努力。尽管吞咽困难是无数神经系统疾病发病率和死亡率的主要来源，但其治疗选择很少。nUro，Inc.（“nUro”）-与Teresa Lever博士（密苏里州大学）合作-正在开发植入式神经刺激技术，为吞咽困难患者提供新的治疗选择。nUro技术的目标是上级喉神经（SLN），该神经主要包含感觉神经纤维，将有关温度、味觉和触觉的信息从喉和咽传递到大脑。从SLN到大脑的神经信号有助于吞咽的顺序运动模式的触发、成形和定时的编排。我们假设，慢性SLN刺激将选择性地促进神经源性吞咽困难患者的吞咽。这项拟议研究的广泛长期目标是将SLN刺激确立为ALS吞咽困难和其他慢性神经系统疾病（导致吞咽困难相关发病率和死亡率）的新型有效预防/恢复治疗。所提出的申请的直接目标是优化ALS小鼠模型中慢性SLN刺激的方案。在这个第一阶段的提案中，我们将通过研究这种创新方法在ALS转基因小鼠模型中维持健康吞咽功能的有效性来证明慢性SLN刺激治疗的可行性。通过在未麻醉的非卧床小鼠中确定适当的治疗参数（具体目标1），并证明ALS受影响的小鼠可以保持健康的吞咽功能，并且由于长期SLN刺激而存活时间显著更长（具体目标2），我们将确立开始研究和开发ALS吞咽困难人类治疗所需的可行性。结果将为使用慢性SLN刺激长期管理ALS和其他慢性神经系统疾病患者的吞咽困难奠定基础，这些疾病会导致吞咽困难相关的发病率和死亡率。