Since 2010, research teams from the CEA's Institut de biologie François Jacob have shown that it is possible to treat patients afflicted with severe forms of beta thalassemia and sickle-cell anemia, two hereditary blood disorders caused by a defect in the hemoglobin beta gene, using gene therapy. While very encouraging, these early achievements concern individuals for whom a sufficient number of target cells are corrected by the therapeutic vector containing a functional version of the hemoglobin beta gene.

It should be noted that the target cells of this therapy are the blood stem cells, known as hematopoietic stem cells (HSCs), which are located in the bone marrow. The researchers have now shown that correction by the therapeutic vector varies according to the HSC. The existence of this variation limits the effectiveness of the strategy. Moreover, too many vector copies may end up in the same cell, which increases the insertion frequency of the gene at inappropriate places in the genome, thus increasing the risk of genotoxicity.

The researchers therefore improved the therapeutic vector so as to give a selective advantage to the corrected HSCs and to limit the number of vector copies by genetically modified HSCs. They verified in vitro that it is possible to obtain 100% of genetically modified cells using one to two copies of the vector. Next, they confirmed in vivo, using mice that were injected with the corrected cells, the strong selection potential of HSCs.

In addition to these new properties, this second-generation vector is produced in an efficient manner and has qualities that are comparable to those of the initial vector (i.e. production and gene transfer efficiency, protocol duration, expression level of the therapeutic gene, etc.). As the selection products already have their marketing authorization, the conditions are in place for the rapid clinical use of the vector. Nevertheless, toxicological studies are still necessary before testing the vector in individuals with severe forms of beta thalassemia or sickle-cell anemia.