The Future of Iron Therapeutics

Therapies for disorders of iron metabolism are rapidly progressing beyond venesection, chelation, and nutritional iron supplementation. Recent research elucidating the molecular and structural biology of systemic iron homeostasis and iron regulation has ushered in a new era in iron therapeutics. As part of this year’s Scientific Program, hematologists will look into the future of the iron metabolism disorder management during the session, “From Structure to Function: Next Generation Iron Therapeutics.”

Here, session chair Sant-Rayn Pasricha, MBBS (Hons), MPH, PhD, previews the discussion, which will cover how the understanding of systemic iron homeostasis has transformed over the past 20 years and what questions remain to be answered.

Can you give us a preview of the session? What topics will the speakers be discussing?

Venesection, chelation, and nutritional iron supplementation have been the traditional therapies for disorders of iron metabolism. However, understanding of the molecular and structural biology of systemic iron homeostasis has rapidly advanced in recent years. These findings are already influencing drug discovery and will yield a new era for iron therapies. In this session, the speakers will traverse the landscape from novel structural insights of iron regulatory molecules through to the current drug development landscape for iron disorders.

First, Aashish Manglik, MD, PhD, will discuss his discoveries of the atomic-level structure of ferroportin and its interaction with hepcidin using cryogenic electron microscopy, providing insights into how these findings will set the stage for the discovery of therapeutic ferroportin modulators. Next, Yvette Yien, PhD, will discuss model organisms that have illuminated how ubiquitous mitochondrial proteins regulate heme synthesis in erythroid cells, as well as strategies for studying the function of critical housekeeping mitochondrial proteins. Finally, Dorine Swinkels, MD, PhD, will discuss the next-generation drugs for iron disorders, including iron deficiency, iron maldistribution, and iron overload of various causes.

So far, how have the recent discoveries in iron homeostasis and iron regulation informed drug discovery?

Over the past two decades, key discoveries in systemic iron homeostasis have revealed the mechanisms regulating iron absorption, transport, uptake at the cells, and export from cells. The first era elucidated many of the essential molecules involved in these processes, such as hepcidin and ferroportin. Most recently, high-resolution structural techniques have shed new light on the precise interactions between these molecules and how they mediate iron regulation. These exciting discoveries are opening the door to a new generation of therapeutics that will eventually transform treatment of iron-related disorders.

What remaining questions need to be answered about these therapeutics?

We have a lot to learn. The first generation of novel therapeutics are entering clinical trials, and they are working as expected in terms of physiology. We will need larger studies to learn their impact on clinical outcomes and their place in the treatment algorithm before they enter widespread clinical use. Improved structural insights will likely give rise to the next generation of drugs, which may have fewer off-target effects.

What do you hope attendees take away from this session?

We hope this session will be exciting for clinical and nonclinical attendees alike. We want to give attendees a new understanding of the atomic-level interactions between key iron regulatory molecules and how these can eventually be harnessed to develop improved treatments for patients. Iron metabolism is a great example from recent years of how discovery of physiologic mechanism has led to therapeutic avenues that will soon benefit patients. This is a journey we want to share with attendees.