Development of Dietary Quercetin to Treat Muscle Wasting Disorders

开发膳食槲皮素治疗肌肉萎缩疾病

• 批准号: 10081511
• 负责人: Brandon VanderVeen
• 金额: $ 30万
• 依托单位: ACEPRE, LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2022-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10081511
• 关键词: Animals; Anti-Inflammatory Agents; Automobile Driving; Behavioral; Biochemical; Biogenesis; Biological Availability; Body Weight; Body Weight decreased; Cachexia; Cancer Patient; Cessation of life; Chemotherapy-Oncologic Procedure; Chronic Disease; Chronic Kidney Failure; Chronic Obstructive Airway Disease; Clinical Trials; Data; Dependence; Development; Diagnosis; Diet; Disease; Disease model; Dose; Drug Kinetics; FDA approved; Fatigue; Fluorouracil; Goals; Health Care Costs; Heart failure; Human; Impairment; Inflammation; Investigation; Investigational Drugs; Length of Stay; Link; Malignant Neoplasms; Mitochondria; Modeling; Mus; Muscle; Muscle Weakness; Muscle function; Muscular Atrophy; New Agents; Oral; Outcome; Pathologic; Patients; Pharmacologic Substance; Phase; Physical Function; Physical Performance; Physiological; Plasma; Positioning Attribute; Property; Quality of life; Quercetin; Reporting; Skeletal Muscle; Small Business Innovation Research Grant; Testing; Thinness; Time; Tissues; Toxic effect; Toxicology; Wasting Syndrome; cancer cachexia; cancer therapy; chemotherapeutic agent; chemotherapy; cost; disease heterogeneity; effective therapy; efficacy study; follow-up; fruits and vegetables; improved; innovation; mitochondrial dysfunction; mortality; muscle form; neuromuscular; physical inactivity; polyphenol; prevent; programs; screening; success; therapy outcome; tumor; wasting

PROJECT SUMMARY: Cachexia, the unintentional loss of body weight, is prevalent in chronic diseases and associated treatments. Cachexia is associated with reduced physical function, decreased tolerance for treatment, and increased mortality. Moreover, a cachexia diagnosis is consistent with a doubling in duration of hospital stay and an additional cost of $4,000/case compared to non-cachectic patients. Cachexia has been reported following chemotherapy treatment including muscle mass loss and fatigue which contribute to reduced quality of life. Furthermore, the loss of lean mass with cachexia impairs chemotherapy treatment tolerance and can exacerbate functional decrements leading to functional dependencies and accrued health care cost. Single and combined chemotherapeutic agents such as 5 fluorouracil (5FU) and FOLFIRINOX have been shown to directly disrupt skeletal muscle mass and function in tumor-bearing mice. Additionally, 5FU and FOLFIRINOX administration in animals and humans induces body weight loss associated with skeletal muscle mass loss and disrupted mitochondrial function, representing as an ideal model to study cachexia. Currently, there are no approved therapies for cachexia despite the improvements in our understanding of the mechanisms underlying muscle wasting. Quercetin, a natural polyphenol found in various fruits and vegetables, has been recognized for its anti-inflammatory properties and its ability to increase mitochondrial biogenesis. We have collected convincing data that support further investigation of Quercetin as an agent to prevent/treat cachexia: 1) we reported that Quercetin can reduce cancer-induced cachexia; 2) we showed that Quercetin can reduce the physical fatigue that is associated with chemotherapy; 3) we reported that Quercetin can increase physical performance by increasing mitochondrial biogenesis; and 4) we showed that Quercetin can reduce inflammation in a number of disease models. However, Quercetin has not yet been developed as an agent to prevent or treat cachexia. Our long-term goal is to move this dietary compound towards human clinical trials as an innovative agent to prevent/treat cachexia. In this Phase I SBIR project we will rigorously test the hypothesis that dietary Quercetin will ameliorate the cancer and chemotherapy-induced cachexia and thereby result in improved therapeutic outcomes. Three specific aims are proposed: 1) evaluate Quercetin’s effects on ameliorating cancer and chemotherapy-induced cachexia, 2) establish the effective plasma and muscle levels and dosing interval for Quercetin, and 3) perform a subchronic oral toxicity screening of Quercetin in mice. The success of our proposed phase I SBIR study will further the development of Quercetin as a new agent to prevent/treat cachexia. A follow-up Phase II SBIR program will expand on these initial studies to: 1) complete efficacy studies of Quercetin using additional models of cachexia; and 2) complete advanced pharmaceutical toxicology studies in mice. The overall goal of Phase II will be to position AcePre LLC for an FDA Pre-Investigational New Drug package.

项目摘要：Cachexia是无意的体重损失，在慢性疾病和相关治疗中普遍存在。恶病质与身体机能降低，治疗耐受性降低以及死亡率增加有关。此外，与非治疗患者相比，卡希克西诊断的诊断与住院期间的增加一倍，额外的成本为4,000美元/案例。在化学疗法治疗后，已有据报道，病虫气包括肌肉质量损失和疲劳，这导致生活质量降低。此外，恶病质的瘦质量损失会损害化学疗法的治疗耐受性，并加剧功能降低，从而导致功能依赖性和累积的医疗保健成本。单一和组合的化学治疗剂，例如5种氟尿嘧啶（5FU）和Folfirinox，已显示出直接破坏骨骼肌质量和肿瘤小鼠的功能。此外，动物和人类中的5FU和FOLFIRINOX给药可引起与骨骼肌质量损失和线粒体功能中断相关的体重减轻，这是研究恶病质的理想模型。目前，尽管我们对肌肉浪费的机制有所改善，但尚无批准的恶病质疗法。槲皮素是一种在各种水果和蔬菜中发现的天然多酚，以其抗炎特性及其增加线粒体生物发生的能力而被认可。我们收集了令人信服的数据，这些数据支持槲皮素作为预防/治疗恶病质的代理的进一步投资：1）我们报告说，槲皮素可以减轻与化学疗法相关的物理疲劳； 3）我们报告说，槲皮素可以通过增加线粒体生物发生来提高身体性能。 4）我们表明槲皮素可以减少许多疾病模型中的炎症。但是，槲皮素尚未作为预防或治疗恶病质的药物开发。我们的长期目标是将这种饮食化合物转向人类的临床试验，作为预防/治疗恶病质的创新药物。在这个I阶段的SBIR项目中，我们将严格检验以下假设：饮食槲皮素将改善癌症和化学疗法诱导的卡氏症，从而改善治疗结果。提出了三个具体目的：1）评估了槲皮素对改善癌症和化学疗法诱导的恶病质的影响，2）建立有效的血浆和肌肉水平，以及槲皮素的剂量间隔，3）进行小鼠中槲皮素的亚chr毒性口服毒性筛查。我们提出的I期SBIR研究的成功将进一步发展槲皮素作为预防/治疗恶病质的新药物的发展。后续II阶段SBIR计划将将这些初步研究扩展为：1）使用其他卡己的模型对槲皮素进行完整的槲皮素研究； 2）在小鼠中完成晚期药物毒理学研究。第二阶段的总体目标是将ACEPRE LLC定位为FDA预先投票的新药套餐。