A novel editing system for precise gene modification – ALGENSICKLE

Precise gene editing based on the homology-directed repair (HDR) repair mechanism holds great promise to manipulate the genome with the goal to correct gene mutations or insert specific DNA sequences. However, several hurdles remain, such as the poor efficiency of HDR-mediated events. Furthermore, in case of failed HDR, the highly efficient non-homologous end joining (NHEJ) DNA repair pathway can prevail and generate unwanted mutations that, for example, could inactivate rather than correct a gene. Here, we will use and optimize a novel proprietary gene editing system designed to improve HDR efficiency and reduce NHEJ-mediated events. We will apply this strategy to correct the genetic mutation causing sickle cell disease (SCD), one of the most common genetic disorders worldwide. SCD is caused by a single point mutation affecting the beta-globin gene, which causes hemoglobin polymerization that strongly affects erythroid cells. In particular, we will test this gene editing system in hematopoietic stem cells (HSCs) from SCD patients. We will evaluate the rescue of the sickle phenotype in the erythroid progeny of genetically modified HSCs and the safety of this therapeutic approach in vitro and in vivo.
This program, which aims to replace the defective beta-globin gene, stands out from several current approaches to the treatment of SCD which instead aim at reactivating fetal hemoglobin expression in adults. Finally, our project also paves the way to the potential treatment of other genetic diseases.