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.

Public Health Relevance

Nutritional deficiencies compromise the wellbeing and developmental health of infants worldwide, including many infants in the United States. Our project will determine the value of an innovative medical food, nutritional yeast modified to express human ferritin, for treating anemia. The core hypothesis is that ferritin will outperform the traditional treatment with ferrous sulfate for delivering iron to the brain, and thus provide a more effective approach to managing iron deficiency and preventing the adverse neurodevelopmental effects of untreated anemia.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Developmental Brain Disorders Study Section (DBD)
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Raiten, Daniel J
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University of Wisconsin Madison
Schools of Arts and Sciences
United States
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Rao, Raghavendra; Ennis, Kathleen; Lubach, Gabriele R et al. (2018) Metabolomic analysis of CSF indicates brain metabolic impairment precedes hematological indices of anemia in the iron-deficient infant monkey. Nutr Neurosci 21:40-48
Rendina, Danielle N; Blohowiak, Sharon E; Coe, Christopher L et al. (2018) Maternal Perceived Stress during Pregnancy Increases Risk for Low Neonatal Iron at Delivery and Depletion of Storage Iron at One Year. J Pediatr 200:166-173.e2
Amaral, Wellington Z; Lubach, Gabriele R; Proctor, Alexandra et al. (2017) Social Influences on Prevotella and the Gut Microbiome of Young Monkeys. Psychosom Med 79:888-897
Dosch, Natalie C; Guslits, Elyssa F; Weber, Morgan B et al. (2016) Maternal Obesity Affects Inflammatory and Iron Indices in Umbilical Cord Blood. J Pediatr 172:20-8
Rendina, Danielle N; Lubach, Gabriele R; Coe, Christopher L (2016) Gestational Timing of Prenatal Disturbance and Fetal Sex Determine the Developmental Outcomes. Neonatology 109:314-20