Novel therapies for obesity- or diabetes-related lymphatic dysfunction

肥胖或糖尿病相关淋巴功能障碍的新疗法

基本信息

批准号：
10602589
负责人：
Mickey Hu
金额：
$ 24.57万
依托单位：
LARIX BIOSCIENCE, LLC
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10602589
关键词：
Address Adipocytes Adult Affect Albumins Angiogenesis Inhibition Animal Model Animals Automobile Driving Biological Assay Blood Vessels C-terminal Cancer Survivor Cell Proliferation Chimeric Proteins Chronic Clinical Data Defect Development Diabetes Mellitus Disease Drug Kinetics Embryonic Development Engineering Exhibits Female Fibrosis Half-Life Hindlimb Hormones Image Immunoglobulin G In Vitro Infection Inflammation Injury Intravenous Drug Abuse Limb structure Liquid substance Lymphangiogenesis Lymphatic Lymphatic Endothelial Cells Lymphatic Endothelium Lymphatic System Mastectomy Measures Mediating Medical Modality Modeling Morbid Obesity Mus Natural regeneration Neoplasms Obesity Pain Patients Pharmaceutical Preparations Phase Plasma Play Population Predisposition Prevalence Proteins RAMP2 RAMP3 Regimen Reporting Research Role Small Business Innovation Research Grant Specificity Survivors Swelling Therapeutic Time Tissues Toxic effect Trauma Treatment Efficacy United States National Institutes of Health Vascular Endothelium Work adrenomedullin adrenomedullin receptor angiogenesis antagonist antiangiogenesis therapy calcitonin receptor-like receptor clinical application commercialization comorbidity efficacy evaluation endothelial dysfunction improved in vivo lymph flow lymphatic circulation lymphatic dysfunction lymphatic vessel male migration mouse model novel novel strategies novel therapeutics obese patients obese person obesity treatment peptide hormone pre-clinical preclinical development programs receptor receptor-activity-modifying protein response side effect stem cell differentiation stem cells tissue stem cells tumor tumor growth

项目摘要

Abstract: Endothelial dysfunction such as lymphatic dysfunction (LD) affects many patients in the U.S. According to a report of the NIH, LD is one of the most poorly understood, relatively underestimated, and least researched complications of diseases or its treatment in the U.S. Secondary LD is caused by an endothelial dysfunction or an acquired defect in the lymphatic system and is commonly associated with obesity, diabetes, infection, neoplasm, trauma, and therapeutic modalities. Although not reported as often as postmastectomy- induced LD, obesity is also one of the most common causes of LD seen in practice in the U.S. today. In the U.S., over 20% of the population (~40 millions) is considered obese. The prevalence of LD in general obese population is relative low; however, an estimated 74% prevalence of LD in morbidly obese patients has been reported. LD is one comorbid condition that has not been well studied in morbidly obese patients, whose population has been increasing year after year. LD may also be associated with intravenous drug abuse. If not properly managed, LD can lead to painful limb swelling, chronic inflammation, tissue fibrosis, and increased susceptibility to serious infection and other diseases. Thus, there is an unmet yet urgent medical need to establish novel anti-LD therapeutics for reducing or overcoming the debilitating effects of LD in the expanding population of LD patients with morbid obesity or diabetes. This research is proposed to tackle this poorly addressed problem. The rationale is based on our findings demonstrating that hormone—adrenomedullin (ADM)—and its cognate receptors, the calcitonin receptor-like receptor (CLR) and receptor activity-modifying proteins (RAMPs), are required for lymphatic vessel development and are necessary and sufficient to reprogram adult tissue stem cells to generate functional lymphatic endothelial cells (LECs). LECs can form new lymphatic vessels to restore lymphatic circulation in LD patients suffering from LD. Wild-type ADM has an extremely short half-life in vivo, limiting its clinical application. Notably, ADM(22–52) functions as a potent ADM-receptor (CLR/RAMP2) antagonist (termed AMRA) for blocking vascular angiogenesis and tumor growth. Thus, we propose creating highly stable proprietary albumin (Alb)-ADM and Fc-ADM fusion proteins as clinical anti-LD therapeutics and Alb-AMRA and Fc-AMRA as proprietary nontoxic anti-angiogenesis/antitumor protein drugs. Specific Aims: (Aim 1) Generate a panel of Alb-ADM and Fc-ADM fusion proteins, characterize the most active fusion proteins using in vitro and in vivo assays, and create Alb-AMRA and Fc-AMRA proteins similarly. (Aim 2) Assess the efficacy and specificity for lymphatic regeneration with combined regimens of Alb- ADM plus Alb-AMRA or Fc-ADM plus Fc-AMRA in the murine models of hindlimb LD, and conduct their toxicity studies in vivo. Significance: After this study, we will identify potent anti-LD regimens ready for preclinical development (e.g., toxicity studies and pharmacokinetics), which will be addressed during Phase II. This work strongly supports Phase II, making this work a compelling and first-in-class anti-LD therapy.

摘要：淋巴功能障碍 (LD) 等内皮功能障碍影响着美国的许多患者。根据 NIH 的一份报告，LD 是最不为人所知、相对被低估且最少的疾病之一。在美国研究的疾病并发症或其治疗方法继发性 LD 是由内皮细胞引起的淋巴系统功能障碍或后天性缺陷，通常与肥胖、糖尿病、感染、肿瘤、创伤和治疗方式，尽管没有像乳房切除术后那样频繁报道。引起的 LD，肥胖也是当今美国实践中最常见的 LD 原因之一。在美国，超过 20% 的人口（约 4000 万）被认为是肥胖者。一般肥胖者中 LD 的患病率。人口相对较少；然而，估计病态肥胖患者的 LD 患病率为 74% 据报道，LD 是一种合并症，尚未在病态肥胖患者中得到充分研究。如果不是的话，LD 人口逐年增加也可能与静脉注射药物滥用有关。如果管理得当，LD 可导致疼痛的肢体肿胀、慢性炎症、组织纤维化和增加因此，存在未满足但紧迫的医疗需求。建立新的抗 LD 疗法，以减少或克服 LD 在扩大中的衰弱作用这项研究旨在解决患有病态肥胖或糖尿病的 LD 患者群体的问题。解决问题的基本原理是基于我们的发现，证明激素——肾上腺髓质素。 (ADM)—及其同源受体、降钙素受体样受体 (CLR) 和受体活性修饰蛋白质（RAMP）是淋巴管发育所必需的，并且是淋巴管发育所必需和充分的重新编程成体组织干细胞以生成功能性淋巴内皮细胞 (LEC)。野生型 ADM 具有恢复 LD 患者淋巴循环的新淋巴管作用。体内半衰期极短，限制了其临床应用。值得注意的是，ADM（22-52）作为一种有效的药物发挥着作用。 ADM 受体 (CLR/RAMP2) 拮抗剂（称为 AMRA）用于阻断血管生成和肿瘤生长。因此，我们建议创建高度稳定的专有白蛋白 (Alb)-ADM 和 Fc-ADM 融合蛋白作为临床抗 LD 疗法以及 Alb-AMRA 和 Fc-AMRA 作为专有的无毒抗血管生成/抗肿瘤蛋白具体目标：（目标 1）生成一组 Alb-ADM 和 Fc-ADM 融合蛋白，表征使用体外和体内测定最活跃的融合蛋白，并创建 Alb-AMRA 和 Fc-AMRA 蛋白（目标 2）评估 Alb- 联合治疗方案对淋巴再生的功效和特异性 ADM加Alb-AMRA或Fc-ADM加Fc-AMRA在小鼠后肢LD模型中，并进行毒性试验体内研究意义：在这项研究之后，我们将确定有效的抗 LD 治疗方案，为临床前做好准备。开发（例如毒性研究和药代动力学），这将在第二阶段工作中得到解决。大力支持 II 期试验，使这项工作成为一种引人注目的一流抗 LD 疗法。