模拟睡眠发作的上呼吸道张力减退急性模型中上呼吸道肌肉的直接光遗传学激活。

IF 5.3 2区 医学 Q1 CLINICAL NEUROLOGY
Sleep Pub Date : 2023-12-11 DOI:10.1093/sleep/zsad226
Fiona L Knapman, E Myfanwy Cohen, Tom Kulaga, Nigel Lovell, Leszek Lisowski, Simon McMullan, Peter G R Burke, Lynne E Bilston
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引用次数: 0

摘要

研究目标:阻塞性睡眠呼吸暂停(OSA)是一种由于扩张器肌肉张力不足而导致上呼吸道在睡眠中反复塌陷的疾病,其治疗具有挑战性,因为目前的治疗方法耐受性差或疗效不稳定且不可预测。我们提出了一种新的基于光遗传学的治疗方法,可以刺激上呼吸道扩张器肌肉对光的反应。为了确定一种新的基于光遗传学的OSA治疗的可行性,我们开发了一种人类睡眠相关上呼吸道肌肉无力的啮齿动物模型。使用该模型,我们评估了候选光遗传学构建体的舌内递送,特别是一种可能具有良好安全性的肌肉靶向方法。方法:将表达由肌肉特异性或非特异性启动子驱动的通道视紫红质-2变体的rAAV血清型9病毒载体注射到大鼠舌头中,以比较视蛋白表达的强度和特异性。在OSA的急性啮齿动物模型中记录了光诱发的肌电图反应。用超声波捕获气道扩张。结果:肌肉特异性启动子产生足够的视蛋白表达,用于光刺激以恢复和/或增强肌电图信号(线性混合模型,F=140.0,P结论:在肌肉特异性启动子驱动的rAAV介导的转导后,对直接光遗传学肌肉激活产生了显著的功能反应,为睡眠期间扩张器肌肉活动不足的患者的光遗传学治疗提供了概念证明。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Direct optogenetic activation of upper airway muscles in an acute model of upper airway hypotonia mimicking sleep onset.

Study objectives: Obstructive sleep apnea (OSA), where the upper airway collapses repeatedly during sleep due to inadequate dilator muscle tone, is challenging to treat as current therapies are poorly tolerated or have variable and unpredictable efficacy. We propose a novel, optogenetics-based therapy, that stimulates upper airway dilator muscle contractions in response to light. To determine the feasibility of a novel optogenetics-based OSA therapy, we developed a rodent model of human sleep-related upper airway muscle atonia. Using this model, we evaluated intralingual delivery of candidate optogenetic constructs, notably a muscle-targeted approach that will likely have a favorable safety profile.

Methods: rAAV serotype 9 viral vectors expressing a channelrhodopsin-2 variant, driven by a muscle-specific or nonspecific promoter were injected into rat tongues to compare strength and specificity of opsin expression. Light-evoked electromyographic responses were recorded in an acute, rodent model of OSA. Airway dilation was captured with ultrasound.

Results: The muscle-specific promoter produced sufficient opsin expression for light stimulation to restore and/or enhance electromyographic signals (linear mixed model, F = 140.0, p < 0.001) and induce visible tongue contraction and airway dilation. The muscle-specific promoter induced stronger (RM-ANOVA, F(1,8) = 10.0, p = 0.013) and more specific opsin expression than the nonspecific promoter in an otherwise equivalent construct. Viral DNA and RNA were robust in the tongue, but low or absent in all other tissues.

Conclusions: Significant functional responses to direct optogenetic muscle activation were achieved following muscle-specific promoter-driven rAAV-mediated transduction, providing proof-of-concept for an optogenetic therapy for patients with inadequate dilator muscle activity during sleep.

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来源期刊
Sleep
Sleep 医学-临床神经学
CiteScore
10.10
自引率
10.70%
发文量
1134
审稿时长
3 months
期刊介绍: SLEEP® publishes findings from studies conducted at any level of analysis, including: Genes Molecules Cells Physiology Neural systems and circuits Behavior and cognition Self-report SLEEP® publishes articles that use a wide variety of scientific approaches and address a broad range of topics. These may include, but are not limited to: Basic and neuroscience studies of sleep and circadian mechanisms In vitro and animal models of sleep, circadian rhythms, and human disorders Pre-clinical human investigations, including the measurement and manipulation of sleep and circadian rhythms Studies in clinical or population samples. These may address factors influencing sleep and circadian rhythms (e.g., development and aging, and social and environmental influences) and relationships between sleep, circadian rhythms, health, and disease Clinical trials, epidemiology studies, implementation, and dissemination research.
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