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Brittenham G.M.,Columbia University | Andersson M.,ETH Zurich | Egli I.,ETH Zurich | Foman J.T.,ETH Zurich | And 4 more authors.
American Journal of Clinical Nutrition | Year: 2014

Background: After the oral administration of iron, the production of circulating non-transferrin-bound iron may contribute to an increased risk of illness in malaria-endemic areas that lack effective medical services. Objective: In healthy women with a range of body iron stores, we aimed to determine effects on the production of circulating non-transferrin-bound iron resulting from the oral administration of 1) a supplemental dose of iron (60 mg) with water, 2) a supplemental dose of iron (60 mg) with a standard test meal, and 3) a fortification dose of iron (6 mg) with a standard test meal. Design: With the use of serum ferritin as the indicator, healthy women with replete iron stores (ferritin concentration >25 μg/L; n = 16) and reduced iron stores (ferritin concentration ≤25 μg/L; n = 16) were enrolled in a prospective, randomized, crossover study. After the oral administration of aqueous solutions of ferrous sulfate isotopically labeled with 54Fe, 57Fe, or 58Fe, blood samples were collected for 8 h, and iron absorption was estimated by erythrocyte incorporation at 14 d. Results: At 4 h, serum non-transferrin-bound iron reached peaks with geometric mean (95% CI) concentrations of 0.81 μmol/L (0.56, 1.1 μmol/L) for 60 mg Fe with water and 0.26 μmol/L (0.15, 0.38 μmol/L) for 60 mg Fe with food but was at assay limits of detection (0.1 μmol Fe/L) for 6 mg Fe with food. For the 60 mg Fe without food, the area under the curve over 8 h for serum non-transferrin-bound iron was positively correlated with the amount of iron absorbed (R = 0.49, P < 0.01) and negatively correlated with serum ferritin (R = 20.39, P < 0.05). Conclusions: In healthy women, the production of circulating non-transferrin-bound iron is determined by the rate and amount of iron absorbed. The highest concentrations of non-transferrin-bound iron resulted from the administration of supplemental doses of iron without food. Little or no circulating non-transferrin-bound iron resulted from the consumption of a meal with a fortification dose of iron. This trial was registered at clinicaltrials.gov as NCT01404533. © 2014 American Society for Nutrition. Source


Schmidt P.J.,Harvard University | Racie T.,Alnylam Pharmaceuticals | Westerman M.,Intrinsic Lifesciences, Llc | Fitzgerald K.,Alnylam Pharmaceuticals | And 2 more authors.
American Journal of Hematology | Year: 2015

β-thalassemias result from diminished β-globin synthesis and are associated with ineffective erythropoiesis and secondary iron overload caused by inappropriately low levels of the iron regulatory hormone hepcidin. The serine protease TMPRSS6 attenuates hepcidin production in response to iron stores. Hepcidin induction reduces iron overload and mitigates anemia in murine models of β-thalassemia intermedia. To further interrogate the efficacy of an RNAi-therapeutic downregulating Tmprss6, β-thalassemic Hbbth3/+ animals on an iron replete, an iron deficient, or an iron replete diet also containing the iron chelator deferiprone were treated with Tmprss6 siRNA. We demonstrate that the total body iron burden is markedly improved in Hbbth3/+ animals treated with siRNA and chelated with oral deferiprone, representing a significant improvement compared to either compound alone. These data indicate that siRNA suppression of Tmprss6, in conjunction with oral iron chelation therapy, may prove superior for treatment of anemia and secondary iron loading seen in β-thalassemia intermedia. © 2015 The Authors. Source


Muller K.F.,University Hospital of Tuebingen | Lorenz L.,University Hospital of Tuebingen | Poets C.F.,University Hospital of Tuebingen | Westerman M.,Intrinsic Lifesciences, Llc | Franz A.R.,University Hospital of Tuebingen
Journal of Pediatrics | Year: 2012

Objectives: To evaluate whether hepcidin concentrations in serum (Hep (S)) and urine (Hep (U)) correlate with iron metabolism, erythropoiesis, and inflammation in preterm infants. Study design: Thirty-one preterm infants (23-32 weeks gestational age) were included. The concentration of the mature, 25 amino-acid form of hepcidin was determined by enzyme-linked immunosorbent assay in serum, urine, blood counts, reticulocytes, and iron measurements. Results: Median (IQR) Hep (S) was 52.4 (27.9-91.9) ng/mL. The highest values were measured in patients with systemic inflammation. Hep (S) and Hep (U) correlated strongly (P =.0007). Hep (S) and Hep (U) also correlated positively with ferritin (P =.005 and P =.0002) and with reticulocyte hemoglobin content (P =.015 and P =.015). Hep (S) and Hep (U) correlated negatively with soluble transferrin receptor/ferritin-ratio (P =.005 and P =.003). Infants with lower hemoglobin concentrations and higher reticulocyte counts had lower Hep (S) (P =.0016 and P =.0089). Conclusion: In sick preterm infants, iron status, erythropoiesis, anemia, and inflammation correlated with the mature 25 amino-acid form of hepcidin. Further evaluation of Hep (U) for non-invasive monitoring of iron status in preterm infants appears justified. Copyright © 2012 Mosby Inc. Source


Patent
Intrinsic Lifesciences, Llc | Date: 2014-03-13

The present application relates to antibodies that specifically bind to hepcidin and methods of using the antibodies. Another aspect relates to antibodies which bind hepcidin and regulate iron homeostasis. Another aspect relates to the use of humanized antibodies which bind hepcidin for the treatment of a disease or condition associated with hepcidin.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 700.34K | Year: 2013

DESCRIPTION (provided by applicant): Acute kidney injury (AKI) is a common, severe complication of cardiopulmonary bypass (CPB) assisted surgeries, and include coronary artery bypass grafts, valve replacements, aortic aneurisms, and organ transplants. Elderly patients, diabetics, and chronic kidney disease (CKD) patients, have very high risk of developing AKI postoperatively. One million CPB surgeries yearly result in thousands of AKI-related deaths and disabilities involving renal replacement therapy (RRT), cumulatively costing billions. Existing renal markers confirming loss of function (e.g. serum creatinine) in AKI are very late markers (1-3 days) for diagnosis of AKI. Few biomarkers (e.g. NGAL, KIM-1) are commercially available for early prediction ofAKI. Early biomarkers and rapid tests predicting the severity of post-CPB AKI will enable patient stratification, earlier therapeutic interventions, and drug development for AKI Recently, we have shown that hepcidin is a small peptide (2.78kD) produced inthe liver and excreted in urine and may be a good biomarker for AKI post CPB-assisted surgery. In two 100 patient clinical trials with our collaborators in Australia (NCT00910221; Prowle et al. 2012) and Germany (NCT00672334; Haase-Felietz et al. 2011), plasma and urine samples were taken at baseline, 6hr and 24hr from baseline. In contrast to established biomarkers of AKI, plasma creatinine (pCr) and neutrophil gelatinase-associated lipocalin (NGAL), in both these studies urinary hepcidin (uHep; ng/ml) anduHep adjusted for urine creatinine (uHep/uCr; ng/mg) was inversely correlated with severity of AKI when scored by RIFLE criteria (based on pCr). AKI-free patients had highly elevated levels of uHep and uHep/uCr at 6hr that increased through 24hr. uHep anduHep/uCr increased 3- to 7-fold compared to patients with AKI (P = 0.004, P = 0.002) at 6hr in the German study with a AUC-ROC 0.80; 0.88, respectively, for prediction of AKI-free recovery and an AUC-ROC 0.81; 0.88, respectively, for prediction of RRT-free recovery. These data support uHep and uHep/uCr as a promising biomarker of AKI-free recovery at 6 hours, much earlier than existing biomarkers such as plasma creatinine, urine output volume, and GFR. However, for a biomarker to be useful for diagnosis ofAKI, it must be measured and the data returned to the surgeon and ICU staff quickly as there are few established clinical interventions for AKI. We propose development of a portable, quantitative lateral flow device (LFD) that can rapidly determine urineand plasma hepcidin concentrations rapidly and quantitatively in the ICU. We have recently discovered and characterized two new mouse anti-hepcidin monoclonal antibodies (MAb) in ongoing SBIR research (PA 08- 114; 2-R44-DK083843-02). For our last submission we made a prototype hepcidin H1 MAb LFD using a gold- conjugated hepcidin tracer that we ultimately abandoned. The specific aims for our revised Phase I research and development efforts are, 1). Assess urinary and plasma hepcidin, NGAL, and KIM-1 in 1800de-identified time-matched samples from a prospective clinical study and perform extensive statistical analysis, and 2) Develop a rapid, quantitative lateral flow device (LFD) suitable for plasma and urine hepcidin and test the new device in the clinicalsamples from the prospective study to evaluate utility of a hepcidin LFD for post-CPB AKI. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: One million Cardiopulmonary Bypass (CPB) surgeries (cardiac grafting, valve replacement, transplants) occur annually and Acute Kidney Injury (AKI) following removal from bypass causes thousands of deaths, longer hospital stays, long-term disabilities, and billions in costs. Current biomarkers cannot predict AKI quickly enough following CPB although new clinical data suggests that urine hepcidin may be a novel, early biomarker of the severity of AKI. Development of a rapid, precise, quantitative lateral flow medical device to measure urine hepcidin in the ICU may allow earlier intervention, novel drugs and therapies to be developed, and valuable clinical benefits to high-risk CPB patients, ultimately saving lives and reducing healthcare costs.

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