AABB Foundation Grant Recipient Spotlight: Antonella Nai, PhD

Antonella Nai, PhD, is a group leader in the regulation of iron metabolism unit within the division of genetics and cell biology at the San Raffaele Scientific Institute in Milan, Italy. Her research focuses on the connection between iron homeostasis and erythropoiesis, with the goal of identifying new therapeutic strategies for anemia and severe malarial anemia. Her work has contributed to the development of therapeutic strategies targeting transmembrane serine protease 6 (TMPRSS6) and transferrin receptor 2 (TFR2), advancing potential new treatments for anemia.

Nai was awarded an AABB Foundation Early-Career Scientific Research Grant in 2018 and was named an AABB Foundation Scientific Research Grant Scholar in 2021. Her project, “Targeting the second transferrin receptor for amelioration of severe malarial anemia,” explores the role of transferrin receptor 2 in regulating erythropoiesis.

Nai spoke with AABB News about the potential impact of her research and how it may shape future therapies for anemia in transfusion medicine and biotherapies.

Your AABB Foundation–supported project focuses on targeting the second transferrin receptor to address severe malarial anemia. What drew you to this approach, and what gap in current treatment does it aim to fill? 

Severe malarial anemia arises from a combination of processes, including parasite-induced hemolysis, accumulation of toxic heme byproducts and a host inflammatory response that suppresses erythropoiesis. Notably, even after parasite clearance, patients often exhibit a blunted response to erythropoietin (EPO), the key driver of red blood cell production, resulting in persistent anemia and increased mortality risk. This highlights a critical gap in current therapies, which primarily target the parasite but do not adequately address impaired erythropoietic recovery. Our approach stems from the idea that restoring the responsiveness of erythroid precursors to erythropoietin could significantly improve outcomes. In this context, we identified transferrin receptor 2 (TFR2) as a negative regulator of erythropoietin signaling and hypothesized that targeting TFR2 could enhance erythropoiesis and promote recovery from anemia.

What do you see as the most meaningful potential impact of this work; what new possibilities could it open for treating severe malarial anemia? 

Our preclinical studies show that selective inactivation of TFR2 in the erythroid compartment delays anemia onset following Plasmodium chabaudi infection, preserves more effective erythropoiesis, and significantly accelerates recovery. Importantly, we also observed a marked reduction in parasitemia in mice lacking hematopoietic TFR2. This suggests that TFR2 targeting may have a dual benefit: improving red blood cell production while simultaneously limiting parasite growth, likely by restricting availability of iron, a key nutrient for parasite replication. This “dual-action” strategy could represent a paradigm shift in treating severe malarial anemia. However, a major next step will be the development of suitable therapeutic tools to selectively target TFR2 in hematopoietic cells.

The Foundation’s support was instrumental in enabling me to pursue this high-risk, innovative idea and to generate the preliminary data necessary for larger funding applications.” 

How might your findings translate to clinical impact, particularly in regions where severe malarial anemia remains a major challenge? 

Although malaria is treatable, it remains a leading cause of morbidity and mortality, particularly in low-resource settings. Current frontline therapies, such as artemisinin-based combination treatments, are highly effective at clearing the parasite but do not address anemia directly, and the emergence of artemisinin resistance is an increasing concern. Our approach offers a complementary strategy: it may not only support erythropoietic recovery increasing EPO sensitivity, but also create a less favorable environment for parasite replication by reducing intracellular iron availability. This could reduce disease severity and potentially mitigate the risk of resistance, making it especially valuable in regions where treatment options are limited.

As both a 2018 AABB Foundation grant recipient and a 2021 scholar recipient, how has the Foundation’s support influenced your work and helped advance this research? 

The Foundation’s support was instrumental in enabling me to pursue this high-risk, innovative idea and to generate the preliminary data necessary for larger funding applications. Without this early support, these initial findings would not have been possible. Importantly, the results obtained through the AABB Foundation awards program helped establish TFR2 targeting as a novel strategy to enhance erythropoiesis across different forms of anemia. This, in turn, allowed me to secure further funding aimed at identifying pharmacological tools to modulate TFR2 function in erythroid cells, an essential step toward translating our findings into clinical applications.

What excites you most about the potential of this work moving forward? 

One of the most exciting next steps is to elucidate the mechanisms by which TFR2 deletion limits parasite growth and modulates iron availability. A deeper understanding of these processes could uncover entirely new therapeutic targets and strategies to prevent drug resistance. Additionally, the development and validation of anti-TFR2 compounds could have broad implications beyond malaria, potentially benefiting patients with other common forms of anemia, such as β-thalassemia, anemia of chronic kidney disease and anemia of inflammation.

Thank You to Our Sponsors