Novel Medical Food for Treating Infant Anemia and Iron Deficiency in the CNS

治疗婴儿贫血和中枢神经系统缺铁的新型医疗食品

• 批准号: 9091601
• 负责人: CHRISTOPHER L COE
• 金额: $ 42.26万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-25 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9091601
• 关键词: Affect; Aftercare; Age-Months; Age-Years; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Anemia; Behavioral; Bioavailable; Biological Assay; Biological Markers; Blood; Blood - brain barrier anatomy; Blood Tests; Brain; Cerebrospinal Fluid; Child; Childhood; Clinical; Clinical Trials; Collaborations; Complex; Consumption; Data; Development; Diet; Dose; Dried Yeast; Effectiveness; Emotional; Experimental Designs; Feedback; Female of child bearing age; Ferritin; Ferrous Sulfate; Food; Food Supplements; Goals; Health; Hematology; Heme; Hemoglobin; Homeostasis; Human; Human Milk; Infant; Infant Health; Injection of therapeutic agent; Intestinal Absorption; Iron; Iron deficiency anemia; Laboratories; Macaca mulatta; Malnutrition; Measures; Meat; Methods; Modality; Modeling; Modification; Monkeys; Motor Activity; Neuraxis; Neurosciences; Nutritional; Oral; Outcome; Outcome Measure; Parents; Pediatric Research; Phase; Prevalence; Prostaglandin D2; Proteins; Proteome; Proteomics; Recording of previous events; Research; Resources; Rodent; Safety; Sampling; Seeds; Serum; Signal Transduction; Staging; Supplementation; Target Populations; Testing; Texture; Therapeutic; Time; Tissues; Toxic effect; Transferrin; United States; Western Blotting; Yeasts; absorption; base; brain health; cognitive performance; feeding; follow-up; fortification; hepcidin; improved; indexing; innovation; iron deficiency; iron supplement; iron supplementation; medical food; metabolome; metabolomics; micronutrient deficiency; neurobehavioral; nonhuman primate; novel; novel therapeutics; prevent; primary outcome; relating to nervous system; response; restoration; standard of care; treatment strategy; uptake

DESCRIPTION (provided by applicant): Iron deficiency is the most common micronutrient deficiency worldwide, and is particularly significant for women of child-bearing age and rapidly growing infants. Conventional methods of treating iron deficiency orally are inadequate as evidenced by poor compliance and the periodic need for iron injections. Our primary goal is to investigate the benefits of a new medical food supplement for treating anemia. We will establish the utility and safety of providing iron in yeast biotechnically modified to express human ferritin One advantage of this modification is that yeast can acquire therapeutic levels of iron in a bioavailable form without significant change in texture or palatability. In addition, ferritin is a highly conserved protein enabling us to provide a natural tissue storage form of iron using yeast as the delivery vehicle. To test its efficacy, we take advantage of a well-characterized nonhuman primate model of infant anemia. Three studies will be conducted in young rhesus monkeys under controlled laboratory conditions, empirically verifying the value of this yeast-ferritin complex in infants, a likely target population in humans. We will directly compare its benefits to a common standard of care: oral treatment with ferrous sulfate. Beyond traditional hematological tests and iron- related measures in serum, several novel endpoints will be determined in cerebrospinal fluid, including quantitation of iron management proteins and two important protein indices previously identified by proteomic analysis to be abnormal in anemic infants. Prior proteome and metabolome analyses revealed that when infant anemia is not resolved, it impacts functional proteins in the developing CNS, including prostaglandin D2 synthase and amyloid beta A4 protein-like, and impairs brain energetics. In addition to verifying the effectiveness of this innovative treatment, we will determine the safety if an iron-sufficient infant were to consume yeast containing iron, a critical prerequisite for human clinical trials. Measures of the heme and intrathecal compartments will be determined before, during, and after treatment. Based on previously found behavioral differences in anemic monkeys, emotional reactivity, motor activity, and cognitive performance will be assessed after supplementation. The core hypothesis is that this yeast-ferritin complex will provide iron in a readily absorbed form, and most significantly, that direct provision of ferritin will replenish the iron-deficient CNS more effectively. Using a multi-tiered nutritional and developmental neuroscience approach, several novel aspects of iron delivery and utilization will be investigated. The research has a clear translational relevance with the potential for establishing a new therapeutic modality. It will set the stage for a Phase I/II clinical trial and, at the same time, validate new biomarkers for tracking how anemia and iron supplementation affect the developing brain. Our capacity to carry out this unique inter-disciplinary project is based on a history of collaboration between two laboratories with the essential resources and expertise.

描述（由申请人提供）：缺铁是全世界最常见的微量营养素缺乏症，对育龄妇女和快速生长的婴儿尤为重要。口服治疗缺铁的常规方法是不充分的，这由依从性差和需要定期注射铁证明。我们的主要目标是研究一种新的医疗食品补充剂治疗贫血的益处。我们将确定在经生物技术修饰以表达人铁蛋白的酵母中提供铁的实用性和安全性。这种修饰的一个优点是酵母可以以生物可利用的形式获得治疗水平的铁，而不会显著改变质地或适口性。此外，铁蛋白是一种 高度保守的蛋白质使我们能够使用酵母作为递送载体来提供铁的天然组织储存形式。为了测试其功效，我们利用了一个特征良好的非人灵长类动物婴儿贫血模型。将在受控实验室条件下在年轻恒河猴中进行三项研究，以经验验证这种酵母铁蛋白复合物在婴儿中的价值，婴儿可能是人类的目标人群。我们将直接将其益处与常见的护理标准进行比较：硫酸亚铁口服治疗。除了传统的血液学检查和血清中的铁相关指标外，还将在脑脊液中确定几个新的终点，包括铁管理蛋白的定量和先前通过蛋白质组学分析确定为贫血婴儿异常的两个重要蛋白质指标。先前的蛋白质组和代谢组分析显示，当婴儿贫血未得到解决时，它会影响发育中的CNS中的功能蛋白，包括前列腺素D2合酶和淀粉样β A4蛋白，并损害大脑能量。除了验证这种创新疗法的有效性外，我们还将确定铁充足的婴儿食用含铁酵母的安全性，这是人体临床试验的关键先决条件。在治疗前、治疗期间和治疗后测定血红素和鞘内隔室的测量值。基于先前在贫血猴中发现的行为差异，将在补充后评估情绪反应、运动活动和认知表现。核心假设是，这种酵母-铁蛋白复合物将以容易吸收的形式提供铁，最重要的是，直接提供铁蛋白将补充铁。 铁缺乏的中枢神经系统更有效。使用多层次的营养和发育神经科学的方法，铁的输送和利用的几个新的方面将进行调查。该研究具有明确的翻译相关性，有可能建立一种新的治疗方式。它将为I/II期临床试验奠定基础，同时验证新的生物标志物，以跟踪贫血和铁补充剂如何影响发育中的大脑。我们开展这一独特的跨学科项目的能力是基于两个实验室之间的合作历史，这些实验室拥有必要的资源和专业知识。