Sickle cell disease

Sickle cell disease is an autosomal recessive disorder affecting millions of people worldwide. Although patient life expectancy has increased over last years, possible acute and chronic complications, which might be seen as an early aging process, can result in premature death at around 40 years. Sickle cell disease is caused by a point mutation in the gene encoding β-globin chains. Mutated sickle hemoglobin (HbS) at low oxygen tension polymerizes leading to irreversible red blood cell sickling and subsequent hemolytic anemia, painful vaso-occlusive crisis and acute chest syndrome. The red blood cell sickling is amplified by primary or secondary inflammation resulting in acute and chronic tissue damage and organ-specific dysfunction.

1. Induction of fetal hemoglobin.

Fetal hemoglobin (HbF) induction therapy significantly reduces sickling in sickle cell disease patients. Hydroxyurea is currently the only FDA approved drug to treat adults with sickle cell disease that induces the expression of HbF. The molecular mechanism of γ-globin expression mediated by hydroxyurea is not fully defined.

It has been demonstrated that hydroxyurea increases the production of nitric oxide on erythroblasts and downstream activation of transcription factors, resulting on γ-globin transcription. Modulation of intracellular levels of the NO second messenger, cyclic guanosine monophosphate (cGMP), may represent a therapeutic target for the treatment of sickle cell disease. We are currently investigating how the soluble guanylate cyclase-cGMP-dependent pathway constitutes a mechanism for the upregulation of γ-globin expression and consequent HbF production in erythroid cells. In addition to its role as the mediator of NO-induced vasorelaxation, cGMP may also be an important mediator of NO-induced inhibition of cellular adhesion, since NO decreases the adhesion of various cell types, including leucocytes and endothelial cells, both in vitro and in vivo.

We are also exploring how oxidative stress regulates human γ-globin gene expression. Oxidative stress is generated by multiple mechanisms, including inflammation and chronic hemolysis, leading to stress erythropoiesis. NRF2 is a master regulator of cellular oxidative stress response and its modulation might be an attractive way to induce HbF and attenuate acute and chronic complications of sickle cell disease.

2. Sickle cell disease and Inflammation

Monocytes, neutrophils, iNKT and platelets have been shown to play a role in these inflammatory processes. Based on our recent clinical observations and experimental work, we ought to define innate as a key player orchestrating acute and chronic complications observed in sickle cell disease. We aim to define new prognostic tools to monitor the development of sickle cell disease complications and novel therapeutic solutions targeting innate immunity, complementary to the classical approaches.

Acute chest syndrome is a life-threatening form of acute lung injury in sickle cell disease, with limited therapeutic options. A role of inflammation induced by hemolysis has been suggested, mediated by activation of lung endothelium and innate immune cells by heme. We recently reported a major IL-6 increase in sputum and bronchoalveolar fluid from children during acute chest syndrome, suggesting a predominant local inflammation. Furthermore, patients with highest IL-6 values had the most severe forms of acute chest syndrome. Our published case report supports a potential benefit of monoclonal antibody therapy against IL-6 for acute chest syndrome resolution. We therefore seek to address an important unmet need for patients, targeting the inflammation induced by heme and modulation of IL-6 activity.

Current treatment strategies as hydroxycarbamide (limiting red blood cell sickling), chronic transfusion and antibiotics, do not fully prevent the progression of life- threating complications. Allogenous stem cell transplantation and gene therapy are not available for the majority of patients. We thus believe that deciphering the unconventional link between red blood cells and inflammatory processes would not only shed light on novel pathophysiological mechanisms, but will also provide new affordable therapeutic strategies of sickle cell disease.

ß-Thalassemia

β-Thalassemia is among one of the most common inherited hemoglobin diseases worldwide in humans. It involves mutations in the beta globin gene leading to deficient hemoglobin production and serious anemia. It represents a heavy burden for patients and a serious global health problem in both developing and modern countries. β-Thalassemia patients present an over production of red blood cell precursors in the bone marrow, which fails to properly maturate into functional red blood cells, a condition knowns as ineffective erythropoiesis.

Beyond the severe anemia, many patients also suffer from multiple organ dysfunctions, largely due to excess iron deposits, known as "iron overload", resulting from the ineffective erythropoiesis and the repeated red blood cell transfusions to address the anemia.

Current clinical management for β-thalassemia includes regular red blood cell transfusions and daily iron chelation therapy, which is associated with toxicities. There are no drugs approved to treat β-thalassemia and healthcare providers have few options for patients. Discovery of common factors contributing to ineffective erythropoiesis and ways to ameliorate it in affected individuals is therefore of clinical importance.

We have previously discovered that GDF11, a TGF-β superfamily member, acts as an autocrine potent inhibitor of erythropoiesis by blocking terminal differentiation of red cell progenitors. Abnormal GDF11 expression in b-thalassemia is dependent on reactive oxygen species, a hallmark of b-thalassemia-associated ineffective erythropoiesis. Surprisingly, this is in sharp contrast with our earlier observations that another ligand of this superfamily, TGF-β1, acts as a strong inducer of terminal differentiation by blocking cell cycle and promoting red blood cell maturation. The molecular bases underpinning the opposite effects of GDF11/TGF-β1 on erythropoiesis are currently being investigated by our group.

Deriving from our previous work, clinical trials demonstrated that targeting GDF11 with ligand traps significantly improve ineffective erythropoiesis, increase hemoglobin levels in non-transfusion-dependent β-thalassemia patients and significantly reduces transfusion burden on transfusion-dependent β-thalassemia patients. Taken altogether this shows that aberrant GDF11 signaling is a key feature of β-thalassemia, and that this pathway is an attractive therapeutic target to correct ineffective erythropoiesis in clinical settings.

Main publications

​​​1) Tocilizumab for severe acute chest syndrome in a child with sickle cell disease and dramatically high interleukin-6 values in endotracheal and pleural fluids. Allali S, Chhun S, de Montalembert M, Heilbronner C, Taylor M, Brice J, Elie J, Rignault-Bricard R, Maciel TT, Chareyre J, Hermine O. Am J Hematol. 2022 Mar 1;97(3):E81-E83. doi: 10.1002/ajh.26433.

2) IL-6 levels are dramatically high in the sputum from children with sickle cell disease during acute chest syndrome. Allali S, de Montalembert M, Rignault-Bricard R, Taylor M, Brice J, Brousse V, Talbot JM, Moulin F, Heilbronner C, Hermine O, Maciel TT. Blood Adv. 2020 Dec 22;4(24):6130-6134. doi: 10.1182/bloodadvances.2020003519.

3) Innate immune cells, major protagonists of sickle cell disease pathophysiology. Allali S, Maciel TT, Hermine O, de Montalembert M. Haematologica. 2020 Jan 31;105(2):273-283. doi: 10.3324/haematol.2019.229989.

4) A novel, highly potent and selective phosphodiesterase-9 inhibitor for the treatment of sickle cell disease. McArthur JG, Svenstrup N, Chen C, Fricot A, Carvalho C, Nguyen J, Nguyen P, Parachikova A, Abdulla F, Vercellotti GM, Hermine O, Edwards D, Ribeil JA, Belcher JD, Maciel TT. Haematologica. 2020 Mar;105(3):623-631. doi: 10.3324/haematol.2018.213462.

5) Plasma histamine elevation in a large cohort of sickle cell disease patients. Allali S, Lionnet F, Mattioni S, Callebert J, Stankovic Stojanovic K, Bachmeyer C, Arlet JB, Brousse V, de Montalembert M, Chalumeau M, Grateau G, Maciel TT, Launay JM, Hermine O, Georgin-Lavialle S. Br J Haematol. 2019 Jul;186(1):125-129. doi: 10.1111/bjh.15900.

6) An activin receptor IIA ligand trap corrects ineffective erythropoiesis in β-thalassemia. Dussiot M*, Maciel TT*, Fricot A, Chartier C, Negre O, Veiga J, Grapton D, Paubelle E, Payen E, Beuzard Y, Leboulch P, Ribeil JA, Arlet JB, Coté F, Courtois G, Ginzburg YZ, Daniel TO, Chopra R, Sung V, Hermine O, Moura IC. Nature Medicine. 2014 Apr;20(4):398-407. doi: 10.1038/nm.3468. * Co-authors