Hemoglobinopathies, namely β-thalassemia and sickle cell disease (SCD), are hereditary diseases, characterized by molecular genetic aberrations in the beta chains of hemoglobin. These defects affect the normal production of hemoglobin with severe anemia due to less or no amount of beta globins in patients with β-thalassemia (quantitative disorder), while SCD is a serious disease in which a mutated form of hemoglobin distorts the red blood cells into a crescent shape at low oxygen levels (qualitative disorder). Despite the revolutionary progress in recent years with the approval of gene therapy and gene editing for specific patients, there is an unmet need for highlighting the mechanisms influencing hemoglobin production and for the development of novel drugs and targeted therapies. The identification of the transcription factors and other genetic modifiers of hemoglobin expression is of utmost importance for discovering novel therapeutic approaches for patients with hemoglobinopathies. The aim of this review is to describe these complex molecular mechanisms and pathways affecting hemoglobin expression and to highlight the relevant investigational approaches or pharmaceutical interventions focusing on restoring the hemoglobin normal function by linking the molecular background of the disease with the clinical perspective. All the associated drugs increasing the hemoglobin expression in patients with hemoglobinopathies, along with gene therapy and gene editing, are also discussed.

Hemoglobin (Hb) Agrinio is a rare non-deletional a-globin mutation observed almost exclusively in Greek, Spanish or other Mediterranean families. The clinical manifestations of a carrier of a single Hb Agrinio mutation (single heterozygosity) depend on the concomitant presence or absence of other mutations or variants in the beta, alpha or other modifying genes. We present a Greek patient harboring a Hb Agrinio variant plus the - -Med alpha deletional allele, having an infrequent severe form of alpha thalassemia, in contrast to the typical alpha thalassemic patient and requiring regular red blood cell (RBC) transfusions and chelation treatment. We also provide a concise literature review regarding alpha thalassemic hemoglobin variants and their molecular and clinical combinations. A phase 2, double-blind, randomized, placebo-controlled, multicenter clinical trial to determine the efficacy and safety of luspatercept (BMS-986346/ACE-536) for the treatment of anemia in adults with alpha thalassemia with the participation of our center is currently recruiting patients (NCT05664737).

Background/Objectives: Sickle cell disease (SCD) is a multi-systemic hemoglobinopathy affecting many patients worldwide. Clinical manifestations include vaso-occlusive (VOC), aplastic, or hemolytic crises. Anemia of a complex etiology is also very common. However, detailed data regarding the level of anemia in Greek or Mediterranean populations with SCD/β-thalassemia are limited. Methods: We retrospectively investigated anemia in 53 SCD patients and described the molecular background regarding mutations in beta and alpha alleles in 49 SCD patients (49/53, representing 92.45% of the cohort). DNA analysis was performed in the Laboratory of Medical Genetics, National and Kapodistrian Athens University. Results: The median age was 50 years (range 18–79 years). A total of 20 patients (38%) were diagnosed with severe anemia (Hgb < 8 g/dL), and 6 patients had a very severe degree of anemia (Hgb < 7 g/dL). On the contrary, four patients had very mild or no anemia, depending on their sex. The median hemoglobin levels of the cohort were 8.72 g/dL (range 6.5–13.3 g/dL), while median reticulocyte levels were 183 K/μL (range 18.35–706 K/μL). We found that patients with the beta zero thalassemic allele had statistically decreased Hgb levels (mean Hgb 8.29 g/dL) and thus a more severe degree of anemia compared with SCD patients with a beta plus allele (mean Hgb 9.48 g/dL, p = 0.010 < 0.05, Student’s t test). Conclusions: Our genotype-stratified analysis characterized the molecular basis of anemia in a well-defined cohort of SCD patients. Clinical trials and future research are essential to investigate possible novel drugs for treating anemia and managing its long-term complications in SCD patients.