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

基本信息

批准号：
8813702
负责人：
CHRISTOPHER L COE
金额：
$ 44.01万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
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/8813702
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 Cognitive 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 Performance Phase Prevalence Proteins Proteome Proteomics Recording of previous events Relative (related person)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 feeding follow-up fortification hepcidin improved indexing innovation iron deficiency iron supplement iron supplementation medical food metabolomics micronutrient deficiency neurobehavioral nonhuman primate novel novel therapeutics prevent primary outcome prostaglandin R2 D-isomerase public health relevance relating to nervous system response restoration standard of care treatment strategy uptake

项目摘要

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）：铁缺乏症是全球最常见的微量营养素缺乏症，对于育龄和快速成长的婴儿而言，尤其重要。口腔治疗铁缺乏症的常规方法不足以证明依从性差和对铁注射的周期需求。我们的主要目标是调查一种新的医疗食品补充剂治疗贫血的好处。我们将建立在酵母生物技术修饰中提供铁以表达人铁蛋白的一种优势的实用性和安全性，即酵母可以以可生物利用形式获得治疗水平的铁水平，而不会显着变化质地或可口。此外，铁蛋白是高度保守的蛋白质使我们能够使用酵母作为输送车提供一种天然组织的储存形式。为了测试其功效，我们利用了婴儿贫血的特征良好的非人类灵长类动物模型。在受控的实验室条件下，将在年轻的恒河猴中进行三项研究，从经验上验证该酵母有铁蛋白复合物在婴儿中的价值，这是人类的可能目标人群。我们将直接将其益处与通用护理标准进行比较：用硫酸亚铁治疗。除了血清中传统的血液学测试和与铁相关的措施外，还将在脑脊液中确定一些新的终点，包括对铁管理蛋白的定量和两个先前通过蛋白质组学分析鉴定的重要蛋白质指数在贫血婴儿中是异常。先前的蛋白质组和代谢组分析表明，当未解决婴儿贫血时，它会影响发育中的CNS中的功能性蛋白质，包括前列腺素D2合酶和淀粉样蛋白βA4蛋白样蛋白，并损害脑能量学。除了验证这种创新治疗的有效性外，我们还将确定是否有足够的富含铁的婴儿食用含铁的酵母，这是人类临床试验的关键先决条件。血红素和鞘内室的测量将在治疗前，期间和之后确定。基于先前发现的贫血猴子的行为差异，将在补充后评估情绪反应性，运动活动和认知表现。核心假设是，这种酵母有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缺陷的CNS更有效。使用多层营养和发育神经科学方法，将研究铁输送和利用的几个新方面。这项研究具有明确的翻译相关性，具有建立新的治疗方式的潜力。它将为I/II期临床试验奠定阶段，同时验证新的生物标志物，以跟踪贫血和铁补充如何影响发育中的大脑。我们执行这个独特的跨学科项目的能力是基于两个实验室与基本资源和专业知识之间的协作历史。