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.

项目摘要/摘要 阻塞性睡眠呼吸暂停（OSA）和肥胖症不足综合征（OHS）是最常见的类型 睡眠失调的呼吸（SDB）。 OSA在美国高度普遍，影响了20-40％ 成年人口和超过50％的肥胖者。大约20％的人 肥胖发展的OHS定义为白天过度ca症和不足衰减，归因于抑郁症 控制呼吸。 OSA和OHS没有有效的药物疗法。我们的总体目标是 为睡眠失调呼吸（SDB）开发一种新颖，安全且有效的治疗方法。我们有 表明脂肪细胞生产的马酮瘦素，可抑制食欲并增加 代谢率，刺激睡眠期间的呼吸。肥胖的个体具有高循环瘦素 水平，但它们对其有益的代谢和呼吸作用具有抵抗力。我们的实验室有 广泛研究小鼠的睡眠和呼吸。我们已经表明，饮食诱发的肥胖症的小鼠 （DIO）开发OHS和OSA，Dospite高血浆瘦素水平。血脑和脑渗透性有限 瘦素的障碍物（BBB）是瘦素耐药性的关键机理。瘦素受体（LEPRB）激动剂 设计用于穿透BBB的设计是有希望的SDB治疗的治疗候选者。 Laszlo博士 OTVOS已开发了LEPRB激动剂E1/ACA，已证明是BBB可渗透的，并且 小鼠和大鼠的体重减轻和代谢功能障碍优于瘦素。我们建立了一个 与Arrevus合作，Arrevus拥有E1/ACA的许可证，并制定了我们的研究计划 为了表征E1/ACA在SDB中的潜在治疗益处。我们将建立重要的 初步数据证明了使用瘦素受体激动剂的概念证明， E1/ACA，治疗SDB。在抗瘦素饮食诱导的肥胖症（DIO）中使用多摄影学 小鼠，将完成两个具体目标，以评估急性（SA1）和慢性（SA2） SDB中E1/ACA的活性。特定的目标1将表征单个的效力 与瘦素相比，SDB上的E1/ACA皮下注射。我们将评估 在（a）OSA严重程度上的E1/ACA升级剂量 与固定剂量的瘦素相比，在睡眠期间的呼吸呼吸症指数和微小的通风； （b） 与肥胖不足（动脉二氧化碳和高碳水化通气反应清醒）相比 固定剂量的瘦素。特定的目标2将表征E1/ACA对SDB的慢性影响 与瘦素相比。我们将评估已鉴定的E1/ACA最佳剂量的效力和安全性 在（a）SDB严重程度为两周的DIO小鼠的AIM 1中； （b）通过评估效果的安全性 CNS，心血管，肺，内分泌和肝毒性的E1/ACA。