World Sickle Cell Day: Hope for treatment with a new gene therapy approach

Severe anemia, painful seizures, increased susceptibility to infections... The symptoms of sickle cell disease affect the daily lives of more than 4 million people worldwide. The most common genetic disease, it is due to a mutation in the globin-β gene that causes an alteration in hemoglobin, responsible for transporting oxygen in red blood cells. Therapeutic advances have been successful in improving the living conditions of patients and increasing their life expectancy, but researchers are continuing their efforts to develop a cure that could be widely available to patients.

Apart from bone marrow transplantation, a few patients have been treated with gene therapy, however, the transport of a functional globin-β gene into target cells is complicated by difficulties in vector production. Annarita Miccio's team from Inserm the University Hospital Necker-Enfants malades AP-HP, the University of Paris, and the Imagine Institute proposes a novel approach to circumvent these difficulties. Instead of replacing the defective globin-β gene, the idea is to activate a replacement gene that is already there, that of globin-γ produced at the time of fetal development. The researchers were inspired by the existence of people who carry the mutation that causes sickle cell disease but do not develop the disease because in their case, globin-γ continued to be produced following a second genetic mutation that cancelled out the effect of the first.

A gene therapy using molecular scissors technology

The blockage of globin-γ expression in adulthood is caused by the modification of a single letter of the DNA chain in the gene containing the information necessary for its production. Deleting this modification, using CRISPR/Cas9 "genetic scissors", would allow to reactivate globin-γ synthesis and correct the sickle cell phenotype in cells.

The researchers have already obtained encouraging results in vitro, in cell culture, with a restoration of globin-γ production at sufficient levels to be considered in future therapeutic protocols. It is now a question of moving on to preclinical trials in order to be able to envisage clinical trials. At the same time, the researcher is waiting for the conclusions of the first trials underway with the Crispr-Cas9 technologies to ensure their safety.

This new approach to gene therapy should eventually benefit a larger number of patients, a major challenge given the number of people concerned.

Annarita Miccio has been awarded one of the prestigious ERC consolidator grants from the European Research Council, which will allow her to benefit from a budget of 2 million euros for 5 years to strengthen her team and advance her research projects more rapidly