Published on 19.06.2023
Sickle cell disease is a genetic disease caused by a mutation in the β-globin gene, which normally combines in groups of 4 molecules to form haemoglobin. The mutated form of globin (known as βS globin) leads to the production of toxic sickle cell haemoglobin (known as HbS). The abnormal shape adopted by this protein deforms the red blood cells, which are then said to be "sickle-shaped", leading to anaemia, painful blood vessel occlusions and an increased risk of infections.
Gene therapy approaches represent a therapeutic solution for these patients. They are based on the transplantation of haematopoietic stem and progenitor cells (responsible for the production of all blood cells, including red blood cells), genetically modified to express the therapeutic βAS globin (known as gene addition), which makes it possible to limit the sickle-shaped deformation of red blood cells. Although promising, these approaches are only marginally effective for sickle cell patients with high and toxic levels of HbS.
In her work published in Molecular Therapy Nucleic Acids, Mégane Brusson from Annarita Miccio's team has developed a new gene therapy approach to enhance treatment efficacy: by simultaneously expressing the therapeutic globin βAS and an artificial microRNA (miRNA) that will specifically reduce HbS levels. This treatment will promote the incorporation of βAS globin into haemoglobin molecules and produce higher quantities of "therapeutic" haemoglobin HbAS.
To achieve this, the team has developed a bi-functional lentiviral vector that carries these two functions. This therapeutic strategy resulted in a substantial reduction in the levels of toxic HbS and a simultaneous increase in the levels of therapeutic HbAS; in corrected red blood cells, this therapeutic haemoglobin enables more effective correction of the sickle cell phenotype, surpassing the effects of the strategy based solely on gene addition.
In addition, they have also shown that this approach does not alter the properties of red blood cells and is stable over the long term, which represent important steps in the development of a therapeutic strategy.
The simultaneous induction of one gene and extinction of a second, using a lentiviral vector, is therefore a highly reliable way of improving the efficacy of the gene therapy approach. This work paves the way for clinical trials to treat sickle cell anaemia, a disease that still affects around 300,000 births a year worldwide.