Martinos Center researcher Eric Gale, PhD, is a recipient of this year’s HMS Blavatnik Therapeutics Challenge Award (BTCA). The BTCA program is designed to accelerate the development of therapeutics within Harvard Medical School (HMS) and its affiliated hospitals, with the specific goal of producing licensable intellectual property within the two-year timeframe of the award.
In his project to be funded by the award, “Sidestepping Iron Restriction to Treat Anemia,” Gale plans to develop a new iron replacement drug for improved treatment of anemias that are complicated by sequestration of iron (also called functional iron deficiency). We checked in with him to learn more about the project.
What was the motivation behind this work?
Chronic kidney disease and other chronic diseases often block iron from traveling to the bone marrow, where it is needed to make red blood cells. Mechanistically, chronic inflammation has a tendency to shut down ferroportin, the only protein that allows iron to pass from inside of cells to the outside, where another protein called transferrin carries the iron to wherever it is needed. When this occurs, the efficacy of drugs used for intravenous iron replacement can be limited.
How so?
Current iron replacement drugs are absorbed and broken down in a type of cell called macrophage, but the iron that is liberated cannot be mobilized from the cell. For many patients, this functional iron deficiency is overcome with drugs called erythropoiesis stimulating agents (ESAs), which work in part by getting the iron moving again. However, these drugs increase the risk of major cardiovascular events. The risk increases with cumulative exposure and ESAs are to be used as sparingly as possible.
How do you propose to address this limitation?
We developed a new kind of drug that releases iron directly and specifically to transferrin—the protein that carries iron around the extracellular spaces and to the bone marrow—effectively skipping the juncture where iron gets stuck. We posit that this drug will enable more effective and safer treatment of iron sequestered anemias. We believe that it could substantially diminish the amount of ESA required to treat anemia of chronic kidney disease, and perhaps eliminate the need for ESA altogether for other iron sequestered anemias.
What led you to this solution?
This project was born out of Martinos Center imaging research. A major focus of mine is developing ‘bio-responsive’ magnetic resonance imaging probes that utilize iron to differentially generate signal in inflamed tissues. As our fMRI colleagues know, iron also has fascinating properties for MRI contrast and can be switched from MR silent to MR visible states depending on its biological surroundings. I was thinking about the biological fate of iron that might leach out of our probes and came to this.