TARGETING TFR2: A NOVEL “ERYTHROPOIESIS-STIMULATING” APPROACH
Violante Olivari1,2, Simona Maria Di Modica1, Mariateresa Pettinato1,2, Maria Rosa Lidonnici3, Jessica
Bordini4, Alessandro Campanella2,4, Giuliana Ferrari2,3, Laura Silvestri1,2 and Antonella Nai1,2
(1)Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Milan, Italy
(2)Vita Salute San Raffaele University, Milan, Italy
(3)San Raffaele-Telethon Institute for Gene Therapy (SR-TIGET),San Raffaele Scientific Institute, Milan,
Italy
(4)Division of Experimental Oncology, San Raffaele Scientific Institute, Milan, Italy
*VO and SMDM contributed equally.
Anemia is a common disorder with multiple etiology. Iron deficiency is the main contributor to the
worldwide burden of anemia, followed by anemia of inflammation (AI). Genetic anemias caused
by mutations in globin genes, as thalassemias, also affect millions of individuals worldwide. AI is
driven by pro-inflammatory cytokines, which reduce the erythroid precursors responsiveness to
erythropoietin (EPO) and stimulate the production of hepcidin that, inhibiting iron absorption to
limit pathogens growth, leads to iron-restricted erythropoiesis. Examples are malarial anemia,
contributed by reduced EPO sensitivity of erythroid precursors and the hemolysis caused by
parasite replication, and chronic kidney disease (CKD) anemia, due to inflammation and
insufficient EPO production that parallels the loss of kidney function.
Treatment with erythropoiesis-stimulating agents (ESA), plus/minus iron, is essential to CKD, and
may be beneficial to some AI and hemolytic anemias. However, indications to ESA are restricted
by the risk of off-target effects due to the EPO-EPOR interaction in non-erythropoietic tissues.
Recently propyl-hydroxylase inhibitors, small-molecules that increase EPO production stabilizing
hypoxia-inducible-factor (HIF), have been proposed as ESA alternatives in CKD. However, the
pleiotropic HIF function raises some safety concerns.
Transferrin Receptor 2 (TFR2), hepcidin activator mutated in type 3 hemochromatosis and partner
of EPOR in erythroid cells, is a negative regulator of erythropoiesis: its selective bone marrow (BM)
inactivation increases EPO responsiveness of erythroid cells, in both wild-type and non
transfusion-dependent beta-thalassemia mice. Hence, we hypothesized that TFR2 might represent
a novel target to potentiate the erythropoietic response in different forms of anemia. Here we
investigate the effect of BM Tfr2 deletion (Tfr2BMKO) in murine models of transfusion-dependent
beta-thalassemia (Hbbth1/th2), CKD and malaria infection.
Hbbth1/th2 mice with BM Tfr2 haploinsufficiency (Tfr2BMhetero/Hbbth1/th2) were generated by
fetal liver cells transplantation into lethally irradiated wild-type mice. After 12 weeks about 50%
of Hbbth1/th2 animals died whereas about 80% of Tfr2BMhetero/Hbbth1/th2 mice
survived. Tfr2BMhetero/Hbbth1/th2 mice showed less severe anemia than Hbbth1/th2, with
increased RBCs and Hemoglobin and reduced ineffective erythropoiesis and cardiomegaly.
Renal damage was induced in Tfr2BMKO mice (obtained through BM transplantation) using an
adenine-rich diet. These mice had enhanced erythropoiesis and maintained RBCs higher than
controls for the entire protocol. Hemoglobin levels were higher in Tfr2BMKOmice for 6 weeks,
while reached control levels at 8 weeks, concomitant with relative hypoferremia, indicating that
BM Tfr2 deletion prevents anemia until iron availability is adequate to the enhanced
erythropoiesis.
Finally, Tfr2BMKO mice injected with Plasmodium Chabaudi Chabaudi infected RBCs had delayed
and reduced parasitemia, lower degree of anemia and maintained a more effective erythropoiesis
than controls.
Overall, our results provide the proof-of-principle for generating anti-TFR2 compounds to be
proposed as novel ESAs. Given the TFR2 restricted expression, these agents are expected to
enhance EPO responsiveness selectively in erythroid cells, reducing the risk of side effects.
SCIENTIFIC PROGRAMME
SESSION I
BONE MARROW
RESPONSE TO VIRAL
INFECTIONS
SESSION II
HAEMATOLOGICAL
RESPONSE TO SARS
COV2 INFECTION
SESSION III
DYSERYTHROPOIESIS IN
CLONAL HAEMOPOIESIS
AND MDS
SESSION IV
ERYTHROPOIESIS
CONTROL
SESSION V
ERYTHROPOIESIS
CONTROL : PHASE 2
SESSION VI
IRON METABOLISM
AND ERYTHROPOIESIS
SESSION VII
INHERITED
DYSERYTHROPOIESIS
SESSION VIII
GENE THERAPY/EDITION
SESSION IX – DRUGS
AND INEFFECTIVE
ERYTHROPOIESIS
SELECTED ABSTRACTS
FOR AN ORAL
PRESENTATION
SELECTED ABSTRACTS
FOR A POSTER
PRESENTATION
FACULTY DISCLOSURES