Investigating ineffective erytrhopoiesis in sickle cell disease – IRIS

Sickle cell disease (SCD) is a genetic recessive inherited disorder caused by a Glu-to-Val substitution in the ß globin protein resulting in abnormal hemoglobin (HbS) that polymerizes under hypoxia driving red cell sickling and reduced half-life. SCD is a severe multisystem disease characterized by hemolytic anemia, high susceptibility to infections, inflammation, recurrent painful vaso-occlusive crises and organ failure. SCD is also characterized by stress erythropoiesis, with abnormalities during terminal erythroid differentiation, suggesting that anemia could also be impacted by defects of central origin. We recently demonstrated the occurrence of ineffective erythropoiesis in the bone marrow of SCD patients and characterized the molecular mechanism as involving the cytoplasmic trapping of HSP70 chaperon protein by HbS polymers under partial hypoxia.
Although SCD has been investigated for decades, there is still an urgent need for more studies to understand the complexity of its molecular and cellular defects and to develop new treatments in a personalized medicine perspective. The main treatments in SCD target the causative defect, i.e. HbS, either by adding normal hemoglobin to the circulation, through chronic blood transfusion or allogeneic hematopoietic stem cell transplantation, or by inducing endogenous fetal hemoglobin (HbF) using hydroxycarbamide (HC). Surprisingly, although HC was first tested in SCD patients more than 35 years ago, the molecular mechanisms underlying its mediated induction of HbF are still poorly understood. HbF expression is a known modulator of disease severity in SCD as it inhibits HbS polymerization, prolonging the lifespan of the red cells in the circulation. Importantly, we have recently revealed a new anti-apoptotic role for HbF during terminal erythroid differentiation in SCD by showing that it rescues erythroblasts from cell death at the polychromatic and orthochromatic stages.
We have designed an ambitious project to address the unknown molecular mechanisms involved in ineffective erythropoiesis in SCD and to test the effect of known and novel therapeutic strategies on erythroid differentiation. In particular, our IRIS project will investigate the (i) molecular bases of ineffective erythropoiesis in SCD related to the auto-oxidation of HbS and to the impaired a and sickle ß chain coupling, and (ii) the impact of erythroblasts’ death on the erythroid niche, particularly on the central macrophage of the erythroblastic island. We will also develop innovative therapeutic strategies based on gene and base editing and assess their effect on ineffective erythropoiesis, together with the effect of other therapeutical molecules such as HC. Our study will be conducted in vitro and in vivo, using a wide panel of tools and human material comprising patient hematopoietic primary cells and cell lines engineered for the project purposes, as well as the humanized Townes SCD mouse model.
The IRIS proposal tackles precedingly unexplored areas of the SCD pathophysiology, both on the fundamental and translational research levels. It will reveal new and important biological aspects of SCD that may explain the large variability in disease severity and degree of anemia. It will also offer new molecular therapeutical strategies that can improve patient life expectancy and quality of life and likely reduce the treatment costs.