Novel therapies for obesity- or diabetes-related lymphatic dysfunction

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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.