Gene therapy for hemoglobinopathies: Clinical trial results and biology of hematopoietic stem cell and the bone marrow niche

Hemoglobinopathies, including beta-thalassemia (Bthal) and sickle cell disease (SCD), are among the most prevalent inherited blood disorders. Genetic mutations affecting hemoglobin synthesis result in severe anemia and multi-organ complications. The development of gene therapy (GT) aimed at correcting or modifying the hematopoietic system, although initially impaired by several limitations, has accomplished the marketing authorization of two hematopoietic stem cell (HSC) medicinal products, engineered by lentiviral vector gene addition and by CRISPR-Cas9 gene editing. Nonetheless, the success of these approaches stimulates a critical revision of our knowledge of HSC biology and bone marrow (BM) microenvironment in these diseases. Here, we review the clinical application of GT by gene addition and gene editing, and the novel findings about HSC and BM niche features and function in hemoglobinopathies. The identification of defective networks in HSC-niche is examined with the perspective of developing combined strategies to ameliorate the BM microenvironment to better support the genetically corrected cells.