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Sickle RBCs cause occlusion of small blood vessels, leading to impaired oxygen delivery to tissues, multiorgan damage, severe pain, and early mortality. 1 Sickle cell disease (SCD) is due to production of a mutant β S-globin forming sickle Hb (HbS α 2β S 2), which has the propensity to polymerize under deoxygenated conditions, resulting in production of sickle-shaped red blood cells (RBCs). In β-thalassemia, reduced (β +) or absent (β 0) β-globin chain production is responsible for precipitation of uncoupled α-globin chains, which, in turn, leads to apoptosis of erythroid precursors and impairment of erythroid differentiation (i.e., ineffective erythropoiesis) and hemolytic anemia. Mutations in the adult β-globin ( HBB) locus lead to abnormal production of the β-globin chain of the adult hemoglobin (HbA α 2β 2) tetramers, causing β-hemoglobinopathies, the most common monogenic disorders worldwide.

In conclusion, the combination of gene addition and gene silencing strategies can improve the efficacy of current LV-based therapeutic approaches without increasing the mutagenic vector load, thus representing a novel treatment for SCD. The bifunctional LV showed a standard integration profile, and neither HSPC viability, engraftment, and multilineage differentiation nor the erythroid transcriptome and miRNAome were affected by the treatment, confirming the safety of this therapeutic strategy.

Efficient transduction of SCD HSPCs by the bifunctional LV led to a substantial decrease of β S-globin transcripts in HSPC-derived erythroid cells, a significant reduction of HbS + red cells, and effective correction of the sickling phenotype, outperforming βAS gene addition and BCL11A gene silencing strategies. Here, we developed a bifunctional LV expressing βAS3-globin and an artificial microRNA (amiRNA) specifically downregulating β S-globin expression with the aim of reducing HbS levels and favoring βAS3 incorporation into Hb tetramers. Transplantation of autologous hematopoietic stem and progenitor cells (HSPCs) transduced with lentiviral vectors (LVs) expressing an anti-sickling β-globin (βAS) is a promising treatment however, it is only partially effective, and patients still present elevated HbS levels. Sickle cell disease (SCD) is due to a mutation in the β-globin gene causing production of the toxic sickle hemoglobin (HbS α 2β S 2).

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