Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Department of Otolaryngology, University of São Paulo, São Paulo, Brazil.
Am J Respir Crit Care Med. 2021 Jan 1;203(1):102-110. doi: 10.1164/rccm.202002-0321OC.
Obstructive sleep apnea is recurrent upper airway obstruction caused by a loss of upper airway muscle tone during sleep. The main goal of our study was to determine if designer receptors exclusively activated by designer drugs (DREADD) could be used to activate the genioglossus muscle as a potential novel treatment strategy for sleep apnea. We have previously shown that the prototypical DREADD ligand clozapine-N-oxide increased pharyngeal diameter in mice expressing DREADD in the hypoglossal nucleus. However, the need for direct brainstem viral injections and clozapine-N-oxide toxicity diminished translational potential of this approach, and breathing during sleep was not examined. Here, we took advantage of our model of sleep-disordered breathing in diet-induced obese mice, retrograde properties of the adeno-associated virus serotype 9 (AAV9) viral vector, and the novel DREADD ligand J60. We administered AAV9-hSyn-hM3(Gq)-mCherry or control AAV9 into the genioglossus muscle of diet-induced obese mice and examined the effect of J60 on genioglossus activity, pharyngeal patency, and breathing during sleep. Compared with control, J60 increased genioglossus tonic activity by greater than sixfold and tongue uptake of 2-deoxy-2-[F]fluoro-d-glucose by 1.5-fold. J60 increased pharyngeal patency and relieved upper airway obstruction during non-REM sleep. We conclude that following intralingual administration of AAV9-DREADD, J60 can activate the genioglossus muscle and improve pharyngeal patency and breathing during sleep.
阻塞性睡眠呼吸暂停是由睡眠期间上气道肌肉张力丧失引起的上气道反复阻塞。我们研究的主要目的是确定设计受体专门激活的设计药物（DREADD）是否可用于激活颏舌肌，作为治疗睡眠呼吸暂停的潜在新策略。我们之前的研究表明，原型 DREADD 配体氯氮平-N-氧化物增加了在下橄榄核表达 DREADD 的小鼠的咽径。然而，需要进行直接的脑干病毒注射和氯氮平-N-氧化物毒性降低了这种方法的转化潜力，并且没有检查睡眠期间的呼吸。在这里，我们利用我们在饮食诱导肥胖小鼠中的睡眠呼吸障碍模型、腺相关病毒血清型 9（AAV9）病毒载体的逆行特性和新型 DREADD 配体 J60。我们将 AAV9-hSyn-hM3（Gq）-mCherry 或对照 AAV9 递送至饮食诱导肥胖小鼠的颏舌肌中，并检查 J60 对颏舌肌活动、咽腔通畅性和睡眠期间呼吸的影响。与对照相比，J60 使颏舌肌的紧张活动增加了六倍以上，2-脱氧-2-[F]氟-D-葡萄糖的舌摄取增加了 1.5 倍。J60 增加了咽腔通畅性并缓解了非快速眼动睡眠期间的上气道阻塞。我们得出结论，在舌内给予 AAV9-DREADD 后，J60 可以激活颏舌肌并改善睡眠期间的咽腔通畅性和呼吸。
