Leptin Receptor Agonist to Treat Sleep Disordered Breathing

瘦素受体激动剂治疗睡眠呼吸障碍

• 批准号: 10599656
• 负责人: Carl Neil Kraus
• 金额: $ 31.99万
• 依托单位: ARREVUS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-05 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10599656
• 关键词: Acute; Adipocytes; Adult; Adverse effects; Affect; Agonist; Anatomy; Apnea; Blood - brain barrier anatomy; Body Weight decreased; Brain; Breathing; Carbon Dioxide; Cardiovascular system; Chronic; Collaborations; Complication; Data; Depressed mood; Desire for food; Dose; Endocrine; Engineering; Exposure to; Goals; Hepatotoxicity; Hormones; Human; Hypercapnia; Hypoventilation; Hypoxemia; Individual; Intranasal Administration; Laboratories; Leptin; Leptin deficiency; Leptin resistance; Licensing; Link; Lung; Metabolic; Metabolic dysfunction; Morbidity - disease rate; Mus; Obese Mice; Obesity; Obstructive Sleep Apnea; Oxygen; Pathogenesis; Penetration; Pharmaceutical Preparations; Pharmacotherapy; Pickwickian Syndrome; Plasma; Polysomnography; Population; Rattus; Recurrence; Research; Resistance; Respiration Disorders; Respiratory Stimulants; Safety; Severities; Sleep; Sleep Apnea Syndromes; Sleep Architecture; Sleep Fragmentations; Subcutaneous Injections; Therapeutic; United States; airway obstruction; awake; blood-brain barrier penetration; blood-brain barrier permeabilization; diet-induced obesity; drug candidate; effective therapy; indexing; intraperitoneal; leptin receptor; metabolic rate; mortality; mouse model; novel; obese person; olfactory bulb; respiratory; response; safety assessment; subcutaneous; therapeutic candidate; ventilation

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.

项目概要/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) 在美国非常普遍，影响 20-40% 的患者。 成年人口中超过 50% 的人患有肥胖症，大约 20% 的人患有肥胖症。 肥胖症发展 OHS 定义为白天高碳酸血症和通气不足，归因于抑郁症 我们的首要目标是控制呼吸。 开发一种新颖、安全、有效的睡眠呼吸障碍 (SDB) 治疗方法。 研究表明，脂肪细胞产生的激素瘦素可以抑制食欲并增加食欲。 新陈代谢率，刺激睡眠期间的呼吸。肥胖者的瘦素循环较高。 水平，但它们对其有益的代谢和呼吸作用具有抵抗力。 研究主要针对小鼠的睡眠和呼吸，我们已经证明小鼠患有饮食引起的肥胖。 尽管血浆瘦素水平较高，但血脑通透性有限，（DIO）仍会出现 OHS 和 OSA。 瘦素屏障（BBB）是瘦素受体（LEPRb）激动剂的关键机制。 Laszlo 博士表示，经过精心设计，可以穿透 BBB，是 SDB 治疗的有希望的候选药物。 Otvos 开发了 E1/Aca，一种 LEPRb 激动剂，已被证明具有 BBB 通透性和 我们建立了一种在小鼠和大鼠的减肥和代谢功能障碍方面优于瘦素的方法。 与拥有 E1/Aca 许可证的 Arrevus 合作，并制定了我们的研究计划 为了描述 E1/Aca 在 SDB 中的潜在治疗益处，我们将建立在显着的基础上。 初步数据证明瘦素受体激动剂的使用概念验证， E1/Aca，使用多导睡眠图治疗瘦素抵抗性饮食诱发肥胖 (DIO)。 小鼠，将完成两个特定目标来评估急性（SA1）和慢性（SA2） SDB 中 E1/Aca 的活性将表征单个目标的效力。 皮下注射E1/Aca对SDB，与瘦素相比我们将评估其效果。 E1/Aca 剂量递增对 (A) OSA 严重程度（氧饱和度指数、呼吸暂停指数）的影响 呼吸不足指数和睡眠期间每分钟通气量）与固定剂量瘦素的比较（B）； 肥胖通气不足（动脉二氧化碳和高碳酸血症通气反应清醒）与 固定剂量的瘦素将表征 E1/Aca 对 SDB 的慢性影响。 我们将评估确定的 E1/Aca 最佳剂量的效力和安全性。 通过评估 DIO 小鼠的目标 1 在两周内对 (A) SDB 严重程度 (B) 安全性的影响； E1/Aca 对中枢神经系统、心血管、肺、内分泌和肝脏的毒性。