Leptin Receptor Agonist to Treat Sleep Disordered Breathing

项目摘要/摘要 阻塞性睡眠呼吸暂停(OSA)和肥胖低通气综合征(OHS)是最常见的类型 睡眠呼吸障碍(SDB)。阻塞性睡眠呼吸暂停综合症在美国非常普遍，影响到20%-40%的 成年人口和50%以上的肥胖个人。约20%的人患有 肥胖会发展成OHS，定义为白天高碳酸血症和呼吸不足，归因于抑郁症 控制呼吸。OSA和OHS尚无有效的药物治疗方法。我们的首要目标是 开发一种新颖、安全、有效的治疗睡眠障碍呼吸(SDB)的方法。我们有 一种脂肪细胞产生的荷尔蒙，瘦素，它抑制食欲，增加 代谢率，刺激睡眠时的呼吸。肥胖者血液中的瘦素水平较高 但它们对其有益的代谢和呼吸影响具有抵抗力。我们的实验室有 广泛研究老鼠的睡眠和呼吸。我们已经证明，饮食诱导肥胖的小鼠 (Dio)发展为OHS和OSA，尽管血浆瘦素水平很高。血脑的有限通透性 瘦素的屏障(BBB)是瘦素抵抗的关键机制。瘦素受体(LEPRb)激动剂 被设计为穿透血脑屏障的药物是SDB治疗的有前景的候选药物。拉兹洛博士 Otvos已经开发出E1/ACA，一种LEPRb激动剂，已被证明具有血脑屏障渗透性和 在小鼠和大鼠的体重减轻和代谢障碍方面优于瘦素。我们建立了一个 与持有E1/ACA许可证的Arrevus合作，并制定了我们的研究计划 探讨E1/ACA在SDB中的潜在治疗优势。我们将在重要的基础上 证明瘦素受体激动剂使用的概念验证的初步数据， E1/ACA，用于治疗SDB。多导睡眠图在瘦素抵抗饮食诱导肥胖(DIO)中的应用 小鼠，将完成两个特定的目标，以评估急性(SA1)和慢性(SA2) SDB中的E_1/ACA活性。具体目标1将描述一个单一目标的效力 皮下注射E1/ACA治疗SDB，与瘦素比较。我们将评估这些措施的效果 (A)阻塞性睡眠呼吸暂停(OSA)严重程度(氧减饱和指数、呼吸暂停 低呼吸指数和睡眠中的分钟通气量)与固定剂量的瘦素进行比较；(B) 肥胖、低通气量(动脉二氧化碳和高二氧化碳呼吸反应清醒)与 固定剂量的瘦素。特定目标2将描述E1/ACA对SDB的慢性影响 与瘦素相比。我们将评估确定的最佳剂量的E1/ACA的有效性和安全性 在DIO小鼠两周期间的目标1中，(A)SDB严重程度；(B)通过评估以下因素的效果来评估安全性 E1/ACA对中枢神经系统、心血管、肺、内分泌和肝脏的毒性。

PROJECT SUMMARY/ABSTRACT Obstructive sleep apnea (OSA) and obesity hypoventilation syndrome (OHS) are the most common types of sleep disordered breathing (SDB). OSA is highly prevalent in the United States, affecting 20-40% of the adult population and more than 50% of individuals with obesity. Approximately 20% of individuals with obesity develop OHS defined as daytime hypercapnia and hypoventilation, attributed to the depressed control of breathing. There is no effective pharmacotherapy for OSA and OHS. Our overarching goal is to develop a novel, safe, and effective treatment for sleep disordered breathing (SDB). We have shown that an adipocyte-produced hormone, leptin, which suppresses appetite and increases metabolic rate, stimulates breathing during sleep. Individuals with obesity have high circulating leptin levels, but they are resistant to its beneficial metabolic and respiratory effects. Our laboratory has extensively studies sleep and breathing in mice. We have shown that mice with diet-induced obesity (DIO) develop OHS and OSA, despite high plasma leptin level. Limited permeability of the blood-brain barrier (BBB) for leptin is a key mechanism of leptin resistance. Leptin receptor (LEPRb) agonists engineered to penetrate the BBB are promising therapeutic candidates for SDB treatment. Dr. Laszlo Otvos has developed E1/Aca, a LEPRb agonist, which has been shown to be BBB permeable and superior to leptin for weight loss and metabolic dysfunction in mice and rats. We established a collaboration with Arrevus, which holds a license to E1/Aca, and developed our research plan to characterize E1/Aca’s potential therapeutic benefit in SDB. We will build upon significant preliminary data to demonstrate a proof-of-concept for the use of the leptin receptor agonist, E1/Aca, to treat SDB. Using polysomnography in leptin-resistant diet-induced obese (DIO) mice, two specific aims will be completed to evaluate the acute (SA1) and chronic (SA2) activity of E1/Aca in SDB. Specific Aim 1 will characterize the potency of a single subcutaneous injection of E1/Aca on SDB, compared to leptin. We will evaluate the effect of escalating doses of E1/Aca on (A) OSA severity (the oxygen desaturation index, the apnea- hypopnea index, and minute ventilation during sleep) compared to a fixed dose of leptin; (B) Obesity hypoventilation (arterial CO2 and the hypercapnic ventilatory response awake) compared to a fixed dose of leptin. Specific Aim 2 will characterize the chronic effects of E1/Aca on SDB compared to leptin. We will evaluate the potency and safety of the optimal dose of E1/Aca identified in Aim 1 in DIO mice over a two-week period on (A) SDB severity; (B) Safety by assessing effects of E1/Aca on CNS, cardiovascular, pulmonary, endocrine, and liver toxicity.