?A major need exists for new treatments for anemias associated with chronic disease states, collectively known as anemia of chronic disease/inflammation (ACDI). These anemias significantly contribute to national morbidity, mortality, and health care expenses. The current treatments are expensive, inconsistently effective, and associated with adverse side effects. The pathogenetic mechanisms of ACDI involve complex perturbations of erythroid homeostasis resulting from inflammatory signaling. A key element in most cases consists of insufficient delivery of iron to bone marrow progenitors: erythroid iron restriction. Accordingly, most current and next-generation therapeutic strategies involve enforcing iron delivery by circumvention of endogenous iron regulatory mechanisms; these approaches thus pose risks of chronic iron overload. Our lab has pioneered an alternative approach to ACDI involving reversal of the erythroid response to iron restriction. This approach exploits the intrinsic ability of erythroid progenitors to regulate global iron metabolism in accordance with erythropoietic demand. Specifically, direct stimulation of erythropoiesis enhances iron absorption and distribution in a physiologic, as-needed manner that avoids iron overload. Accordingly, we have identified aconitase enzyme inactivation as a mediator of the erythroid iron restriction response and have demonstrated reversal of this response by providing the downstream metabolite isocitrate. The therapeutic potential of isocitrate has been demonstrated in several rodent model systems including: murine iron deficiency, rat chronic arthritis, murine chronic arthritis, and murine acute inflammation. Therapeutic targeting of the aconitase-isocitrate pathway in ACDI offers an alternative approach to IV iron or hepcidin inhibition, providing advantages of lower cost, no risk of iron overload, and oral bioavailability. This approach has been validated in multiple animal models, and key elements of the mechanism have now been identified. The proposed studies will compare isocitrate and a series of analogs in a murine arthritis model of ACDI for treatment optimization and characterization of pharmacologic properties.

Public Health Relevance

New treatments are needed for anemias associated with chronic diseases and inflammation. A critical factor contributing to these anemias is impaired iron delivery to the red cell precursors in the bone marrow. When iron delivery to these cells is compromised, signals are triggered which render these cells sensitive to growth inhibition by inflammation and insensitive to growth stimulation by erythropoietin. We have identified an orally active compound, isocitrate that blocks the iron-deprivation signals and enables red cell precursors to develop despite adverse conditions. Isocitrate treatment consistently corrects anemia in rodents with chronic arthritis and thus shows potential as a new therapy for human anemia. The proposed studies will establish the mechanism of action of isocitrate in cell culture and animal models. These studies will further address the suitability of this treatment for anemia in primates.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK101550-03
Application #
9455679
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Roy, Cindy
Project Start
2016-04-01
Project End
2019-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Virginia
Department
Pathology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Khalil, Shadi; Delehanty, Lorrie; Grado, Stephen et al. (2018) Iron modulation of erythropoiesis is associated with Scribble-mediated control of the erythropoietin receptor. J Exp Med 215:661-679
Khalil, Shadi; Holy, Maja; Grado, Stephen et al. (2017) A specialized pathway for erythroid iron delivery through lysosomal trafficking of transferrin receptor 2. Blood Adv 1:1181-1194