Pharmacological and molecular approaches for the treatment of β‐hemoglobin disorders

Abstract

β-hemoglobin disorders, such as β-thalassemia and sickle cell anemia are among the most prevalent inherited genetic disorders worldwide. These disorders are caused by mutations in the gene encoding hemoglobin-β (HBB), a vital protein found in red blood cells (RBCs) that carries oxygen from lungs to all parts of the human body. As a consequence, there has been an enduring interest in this field in formulating therapeutic strategies for the treatment of these diseases. Currently, there is no cure available for hemoglobin disorders, although, some patients have been treated with bone marrow transplantation, whose scope is limited because of the difficulty in finding a histocompatible donor and also due to transplant-associated clinical complications that can arise during the treatment. On account of these constraints, reactivation of fetal hemoglobin (HbF) synthesis holds immense promise and is a viable strategy to alleviate the symptoms of β-hemoglobin disorders. Development of new genomic tools has led to the identification of important natural genetic modifiers of hemoglobin switching which include BCL11A, KLF1, HBSIL-MYB, LRF, LSD1, LDB1, histone deacetylases 1 and 2 (HDAC1 and HDAC2). miRNAs are also promising therapeutic targets for development of more effective strategies for the induction of HbF production. Many new small molecule pharmacological inducers of HbF production are already under pre-clinical and clinical development. Furthermore, recent advancements in gene and cell therapy includes targeted genome editing and iPS cell technologies, both of which utilizes a patient's own cells, are emerging as extremely promising approaches for significantly reducing the burden of β-hemoglobin disorders.

<p>Nucleic Acid Therapy for β-Thalassemia</p>

“…Several studies have investigated the possibility to downregulate their expression as a treatment for β-thalassemia. 9 , 80 , 81 Two powerful tools, RNAi and gene editing technology, are employed to disrupt the BCL11A gene. In vitro study in CD34+ derived erythroid cells demonstrated ability of siRNA to inhibit BCL11A production and successfully increased the HbF levels.…”

Beyond transfusion therapy: new therapies in thalassemia including drugs, alternate donor transplant, and gene therapy

“…Other targets for HbF manipulation, such as SOX3, KLF1, HBSL1-MYB intergenic region, DRED complex (TR2 and TR4), and Lim domain biding 1 have yet to be evaluated clinically. 29 Modulation of GDF11 with activin receptor traps, sotatercept and luspatercept…”

Efficacy of Ruxolitinib as Inducer of Fetal Hemoglobin in Primary Erythroid Cultures from Sickle Cell and Beta-Thalassemia Patients

“…For this reason the search of new inducers of foetal haemoglobin production is important and many new small molecule are under pre-clinical and clinical development. 8 Primary erythroid cultures is an ex vivo system that recapitulates the process of erythropoiesis that in vivo occurs in bone marrow. Starting from the peripheral blood hematopoietic stem cells this system reproduces the differentiation of erythroid precursors to mature erythrocyte and is a good model for analyzing human erythroid cells and their functions.…”