New Therapeutic Options: Alternates to Gene Therapy for Treating Hemoglobinopathies

Hemoglobinopathies are chronic, invalidating globally distributed hereditary red cell disorders, which impact patient survival and quality of life. Sickle cell disease (SCD) and β-thalassemias are the more frequent hemoglobinopathies worldwide. In both SCD and β-thalassemias, novel therapeutic strategies might be divided into (1) pathophysiology related therapies and (2) innovative curative therapeuties such as hematopoietic stem cell transplantation and gene therapy, the latter discussed in another presentation in this session. In the last two decades, studies have highlighted the biocomplexity of SCD and β-thalassemias and the need for the development of new therapeutic options targeting one or more of the mechanisms involved in their pathogenesis. In SCD, the pathophysiology related novel therapies might be divided into: (i)Molecules targeting sickling and red cell dehydration; (ii) Molecules targeting SCD vasculopathy and sickle cell-endothelial adhesive events; (iii) Molecules modulating SCD related oxidative stress. Since inflammatory vasculopathy is a key factor in SCD related organ damage, major efforts have been made to develop agents that interfere with SCD vasculopathy and adhesion events, involving sickle red cells, neutrophils and endothelial interplay. β-thalassemic syndromes are characterized by ineffective erythropoiesis, which plays a crucial role in anemia and in the development of extramedullar erythropoiesis. In β-thalassemic syndromes, pathophysiology related novel therapies might be divided into: (i) Agents reducing the ineffective erythropoiesis such the TRAP ligands, targeting the GDF11 pathway (sotatercept or luspatercept); (ii) Agents affecting Jak2 activation to reduce splenomegaly in β-thalassemia and (iii) Agents modulating hepcidin - erythropoiesis axis such as minihepcidins. The main goal of these molecules is to ameliorate the ineffective erythropoiesis resulting in increased hemoglobin levels with reduction of transfusion requirement, iron overload, and facilitating iron chelation therapy. This review highlights new therapeutic strategies in SCD and β-thalassemia and discusses future development, research implications, and possible directions toward future clinical trials.