Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by degeneration of motor neurons and muscles, and death is usually a result of impaired respiratory function due to loss of motor neurons that control upper airway muscles and/or the diaphragm. Currently, no cure for ALS exists and treatments to date do not significantly improve respiratory or swallowing function. One cause of ALS is a mutation in the superoxide dismutase-1 (SOD1) gene; thus, reducing expression of the mutated gene may slow the progression of the disease. Our group has been studying the SOD1^G93A transgenic mouse model of ALS that develops progressive respiratory deficits and dysphagia. We hypothesize that solely treating the tongue in SOD1 mice will preserve respiratory and swallowing function, and it will prolong survival. At 6 weeks of age, 11 SOD1^G93A mice (both sexes) received a single intralingual injection of gene therapy (AAVrh10-miR^SOD1). Another 29 mice (both sexes) were divided into two control groups: (1) 12 SOD1^G93A mice that received a single intralingual vehicle injection (saline); and (2) 17 non-transgenic littermates. Starting at 13 weeks of age, plethysmography (respiratory parameters) at baseline and in response to hypoxia (11% O₂) + hypercapnia (7% CO₂) were recorded and videofluoroscopic swallow study testing were performed twice monthly until end-stage disease. Minute ventilation during hypoxia + hypercapnia and mean inspiratory flow at baseline were significantly reduced (p < 0.05) in vehicle-injected, but not AAVrh10-miR^SOD1-injected SOD1^G93A mice as compared with wild-type mice. In contrast, swallowing function was unchanged by AAVrh10-miR^SOD1 treatment (p > 0.05). AAVrh10-miR^SOD1 injections also significantly extended survival in females by ∼1 week. In conclusion, this study indicates that intralingual AAVrh10-miR^SOD1 treatment preserved respiratory (but not swallowing) function potentially via increasing upper airway patency, and it is worthy of further exploration as a possible therapy to preserve respiratory capacity in ALS patients.

中文翻译：

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AAVrh10-miRSOD1 的舌内给药可改善肌萎缩侧索硬化超氧化物歧化酶-1 小鼠模型的呼吸功能但不改善吞咽功能。

肌萎缩侧索硬化 (ALS) 是一种以运动神经元和肌肉退化为特征的致命疾病，死亡通常是由于控制上呼吸道肌肉和/或横膈膜的运动神经元丧失导致呼吸功能受损的结果。目前，没有治愈 ALS 的方法，迄今为止的治疗也没有显着改善呼吸或吞咽功能。ALS 的一个原因是超氧化物歧化酶-1 ( SOD1 ) 基因的突变；因此，减少突变基因的表达可能会减缓疾病的进展。我们小组一直在研究ALS的SOD1 ^G93A转基因小鼠模型，该模型出现进行性呼吸缺陷和吞咽困难。我们假设仅在SOD1 中治疗舌头小鼠将保留呼吸和吞咽功能，并延长存活时间。在 6 周龄时，11 只SOD1 ^G93A小鼠（两性）接受了单次舌内注射基因疗法（AAVrh10-miR ^SOD1）。另外 29 只小鼠（两性）被分成两个对照组：（1）12只接受单次舌内载体注射（盐水）的SOD1 ^G93A小鼠；(2) 17 只非转基因同窝仔。从 13 周龄开始，基线体积描记（呼吸参数）和对缺氧 (11% O ₂ ) + 高碳酸血症 (7% CO _{2) 的反应}) 被记录并且电视荧光镜吞咽研究测试每月进行两次直到疾病末期。与野生型小鼠相比，注射 载体但注射 AAVrh10-miR ^{SOD1 的}SOD1 ^G93A小鼠在缺氧 + 高碳酸血症期间的分钟通气量和基线时的平均吸气流量显着降低（p < 0.05）。相比之下，AAVrh10-miR ^SOD1处理未改变吞咽功能（p  > 0.05）。AAVrh10-miR ^SOD1注射也显着延长了女性的生存期约 1 周。总之，本研究表明语内 AAVrh10-miR ^SOD1治疗可能通过增加上呼吸道通畅来保留呼吸（但不是吞咽）功能，作为一种可能的治疗方法来保留 ALS 患者的呼吸能力，值得进一步探索。