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

• 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
• 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

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美国的许多患者 根据NIH的报告，LD是最熟悉的，相对低估的，最少的之一 研究的疾病并发症或美国次要LD的治疗是由内皮引起的 功能障碍或淋巴系统中获得的缺陷，通常与肥胖，糖尿病， 感染，肿瘤，创伤和治疗方式。虽然没有报告过横向切除术的频率 诱导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400万）被认为是肥胖的。一般肥胖中LD的患病率 人口相对低；但是，估计病态肥胖患者的LD患病率估计为74％ 报告。 LD是一种合并症，在病态肥胖的患者中尚未很好地研究 人口年复一年。 LD也可能与静脉药物滥用有关。如果不 正确管理的LD可以导致肢体肿胀，慢性感染，组织纤维化和增加 对严重感染和其他疾病的敏感性。那是一种未满足但紧急的医疗需求 建立新型的抗世界疗法来减少或克服LD在扩展中的衰弱作用 患有病态肥胖症或糖尿病的LD患者人群。提出这项研究是为了解决这一糟糕的问题 解决的问题。基本原理是基于我们的发现，证明了Horsene-肾上腺肾上腺素 （ADM）及其同源受体，降钙素受体样受体（CLR）和受体活性修饰 淋巴管发育所必需的蛋白质（坡道）是必要的，足以 重编程成年组织干细胞以产生功能性淋巴内皮细胞（LEC）。 LEC可以形成 新的淋巴视频以恢复患有LD的LD患者的淋巴循环。野生型ADM有一个 体内半衰期极短，限制了其临床应用。值得注意的是，ADM（22-52）起着有效的作用 ADM受体（CLR/RAMP2）拮抗剂（称为AMRA）用于阻断血管血管生成和肿瘤生长。 这，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LLD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 毒品。具体目的：（目标1）生成一组Alb-ADM和FC-ADM融合蛋白，表征了 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 相似地。 （AIM 2）评估使用ALB-联合方案的淋巴再生的效率和特异性 ADM Plus Alb-Amra或FC-ADM以及Hindlimb Ld的鼠模型中的FC-AMRA，并进行毒性 体内研究。意义：在这项研究之后，我们将确定准备临床前的潜在抗LLD方案 开发（例如，毒性研究和药代动力学），将在第二阶段进行解决。这项工作 强烈支持II期，使这项工作成为引人入胜且一流的抗LLD治疗。