Gene Therapy for Upper Airway and Respiratory Insufficiency in an ALS Mouse Model

ALS 小鼠模型中上气道和呼吸功能不全的基因治疗

• 批准号: 9166838
• 负责人: Mai ElMallah
• 金额: $ 23.78万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9166838
• 关键词: Address; Adult; Affect; Amyotrophic Lateral Sclerosis; Area; Aspiration Pneumonia; Astrocytes; Automobile Driving; Biochemical; Breathing; Cause of Death; Cells; Cessation of life; Clinic; Clinical Trials; Complex; Coupled; Coupling; Data; Deglutition; Dependovirus; Deterioration; Diagnosis; Disease; Distal; Efferent Neurons; Evaluation; FDA approved; Genes; Glutamates; Goals; Human; Impairment; Injection of therapeutic agent; Intervention; Intramuscular; Life; Limb structure; Lung; Methods; MicroRNAs; Molecular; Motor; Motor Neuron Disease; Motor Neurons; Mus; Muscle; Muscle Weakness; Mutate; Mutation; Nerve; Neurodegenerative Disorders; Neuroglia; Neuromuscular Junction; Neurons; Onset of illness; Outcome Measure; Output; Pathology; Patients; Peripheral; Pharmaceutical Preparations; Physiological; Physiology; RNA Interference; Recombinant adeno-associated virus (rAAV); Recurrence; Respiratory Diaphragm; Respiratory Failure; Respiratory Insufficiency; Respiratory Mechanics; Respiratory Muscles; Respiratory System; Respiratory Therapy; Respiratory physiology; Riluzole; Rodent; SOD1 gene; Series; Skeletal Muscle; Speech; Spinal; Symptoms; Technology; Testing; Therapeutic; Transgenic Mice; Translating; Upper Respiratory System; Work; abstracting; behavior test; clinically relevant; experience; gene therapy; improved; inhibitor/antagonist; innovation; mouse model; mutant; neurophysiology; novel; overexpression; pre-clinical; presynaptic; research study; respiratory; superoxide dismutase 1; targeted treatment

Project Summary/Abstract Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease that initially manifests with either bulbar or spinal (limb) symptoms. Bulbar involvement leads to speech and swallowing impairment and recurrent aspiration pneumonia. Death due to respiratory failure occurs within 2-3 years for patients with bulbar onset ALS and 3-5 years for limb onset cases. To date, no treatment exists for this relentless and fatal disease. The only FDA approved drug for ALS is Riluzole – a glutamate release inhibitor which minimally increases life by 3-5 months. As diaphragm and respiratory muscle weakness progress, targeted respiratory therapy with non-invasive ventilatory support improves survival. Therefore, the goal of this proposal is to use gene therapy to target the respiratory system (upper airway, diaphragm and intercostals) in a popular ALS mouse model – the SOD1G93A mouse and assess if this improves breathing and survival. This application proposes to study the impact of respiratory directed gene therapy on spontaneous breathing, pulmonary mechanics, and respiratory efferent nerve output. Adeno- associated virus (AAV) gene therapy coupled with microRNA that silences SOD1 (miRSOD1) will be delivered through retrograde transduction to the entire motor unit (muscle, neuromuscular junction, nerve and motor neurons). In addition, this proposal aims to study the impact of respiratory targeted and systemic gene therapy on pulmonary physiology and neurophysiology outcome measures as well as behavioral testing and survival. Thus, the fundamental hypothesis driving this proposal is that AAV- miRSOD1 gene therapy targeting the upper airway and respiratory system will enhance breathing in the ALS SOD1G93A murine model; and when coupled with systemic delivery of AAV, will improve respiratory function, mobility and prolong survival. Two specific aims are proposed: Aim 1 will test the hypothesis that an intralingual and intrathoracic injection of AAV-miRSOD1 will effectively transduce the entire hypoglossal and phrenic motor units and stimulate respiratory drive. Aim 2 will test the hypothesis that systemic AAV-miRSOD1 delivery coupled with respiratory targeted therapy will halt degeneration, improve survival and enhance respiratory function. Project Relevance: This work is innovative because it will use gene therapy to target respiratory insufficiency (the main cause of death in ALS patients) in an ALS mouse model. The impact of this therapy will be assessed using translational pulmonary outcome measures with the ultimate goal of translating this therapy to the clinic. AAV gene therapy is now in clinical trials and if successful, this therapy will provide a therapeutic option for respiratory failure in the patients with mutations in the SOD1 gene.

项目总结/摘要 肌萎缩侧索硬化症（ALS）是一种破坏性的神经退行性疾病， 表现为延髓或脊髓（肢体）症状。延髓受累导致言语， 吞咽障碍和复发性吸入性肺炎。因呼吸衰竭死亡 延髓型ALS患者在2-3年内发生，肢体型病例在3-5年内发生。 迄今为止，还没有治疗这种无情和致命的疾病的方法。FDA唯一批准的药物 用于ALS的是阿舒唑-一种谷氨酸释放抑制剂，其最低限度地延长寿命3-5个月。 随着膈肌和呼吸肌无力的进展， 非侵入性的辅助支持提高了存活率。因此，本提案的目标是利用 基因治疗靶向呼吸系统（上呼吸道，横膈膜和肋间）， 流行的ALS小鼠模型-SOD 1G 93 A小鼠，并评估这是否改善了呼吸， 生存本申请提出研究呼吸定向基因治疗对肺腺癌的影响。 自主呼吸、肺力学和呼吸传出神经输出。腺- 相关病毒（AAV）基因疗法与沉默SOD 1（miRSOD 1）的microRNA相结合， 通过逆行传导传递到整个运动单位（肌肉、神经肌肉 连接、神经和运动神经元）。此外，本建议旨在研究 呼吸系统靶向和系统性基因治疗对肺生理学和神经生理学的影响 结果测量以及行为测试和存活率。因此， 推动这一提议的假设是靶向上呼吸道的AAV-miRSOD 1基因治疗 和呼吸系统将增强ALS SOD 1G 93 A鼠模型中的呼吸; 再加上AAV的全身递送，将改善呼吸功能、活动性和延长 生存提出了两个具体的目标：目标1将测试假设，一个语内和 胸腔内注射AAV-miRSOD 1将有效地阻断整个舌下神经， 膈运动单位和刺激呼吸驱动。目标2将检验系统性 AAV-miRSOD 1递送与呼吸靶向治疗相结合将阻止变性，改善 存活和增强呼吸功能。项目相关性：这项工作是创新的，因为 它将使用基因疗法来治疗呼吸功能不全（ALS的主要死因 患者）在ALS小鼠模型中。该疗法的影响将使用 转化肺部结局指标，最终目标是将该治疗转化为 诊所AAV基因疗法目前正处于临床试验阶段，如果成功，这种疗法将提供一种新的治疗方法。 SOD 1基因突变患者呼吸衰竭的治疗选择。