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Hepcidin Antagonist Therapy for Anemia of Chronic Disease

Award Number: R43HL132692
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/09/2016
PERIOD OF PERFORMANCE END DATE: 08/31/2018

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Hepcidin Antagonist Therapy for Anemia of Chronic Disease - ¿ DESCRIPTION (provided by applicant): The anemia of chronic disease (ACD; anemia of inflammation) is commonly observed in chronic inflammatory states and may hinder patient recovery and survival. Induction of hepcidin, mediated by IL-6, leads to iron-limited erythropoiesis and anemia (Gardenghi, 2014). Iron homeostasis (reviewed by Ganz, 2012) depends on regulated absorption and transport of dietary iron by means of the iron-transport protein ferroportin and its regulatory peptide, hepcidin. All iron-releasing cells, including enterocytes, macrophages, and hepatocytes, contain ferroportin. Ferroportin activity is controlled by hepcidin. Upon binding hepcidin, ferroportin is internalized and degraded (Fig. 1). When hepcidin concentrations are high, ferroportin degradation exceeds its rate of synthesis, and ferroportin is lost from cell membranes. Without ferroportin, macrophages fail to release iron recycled from senescent erythrocytes, and hepatocytes retain stored iron. Ongoing erythropoiesis depletes extracellular iron within hours. Conversely, when hepcidin concentrations are low, ferroportin synthesis exceeds its degradation, ferroportin re-accumulates in cell membranes, and increased amounts of iron flow from iron-exporting cells into the extracellular fluid. In ACD, excessive hepcidin prevents iron mobilization for erythropoiesis. Recently, an erythroid factor, erythroferrone (ERFE) was discovered to down-regulate hepcidin in response to erythropoietic stimuli. The size and composition of ERFE will lead to a short plasma half-life and will limit its chronic use. Therefore, in this Phase I project we will construct a fusion protein containing ERFE fused to the human IgG4 Fc domain. Fc fusion proteins have extended plasma half-lives due to recycling by the FcRN receptor. We will verify that the Fc fusions are active by measuring hepcidin down-regulation in vitro evaluate the ability of ERFE-Fc to increase serum iron levels in mice. In addition, we will carry out preliminary pharmacokinetic experiments to determine plasma half-life. Phase 2 will focus on obtaining the preclinical data necessary for submission of an IND. We expect ERFE-Fc to address the unmet need of a rational therapy for the anemia of chronic disease.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2019 ( Subtotal = -$8,200 )
2019	2016	PANORAMA RESEARCH	1230 BORDEAUX DR	SUNNYVALE	CA	94089	SANTA CLARA	USA	Blood Diseases and Resources Research	000	1	1/23/2019	NEW	-$8,200
														Subtotal = -$8,200

Issue Date FY: 2016 ( Subtotal = $224,981 )
2016	2016	PANORAMA RESEARCH, INC	2462 WYANDOTTE STREET	MOUNTAIN VIEW	CA	94043	SANTA CLARA	USA	Cardiovascular Diseases Research	000	1	9/8/2016	NEW	$224,981
														Subtotal = $224,981

Grand Total All Awards = $216,781

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Hepcidin Antagonist Therapy for Anemia of Chronic Disease

Award Number: R43HL132692

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/09/2016

PERIOD OF PERFORMANCE END DATE: 08/31/2018

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