Understanding transcriptional and epigenetic control by Gfi1b towards the development of a therapy for sickle cell disease

Sickle cell disease is among the most common genetic disease in Canada and the world. Sickle cell disease is severe and inheritable that frequently start in the first year of life and lead to recurrent hospitalizations, with the risk of organ failure and premature death. Although it is known that the underlying cause for this disease is an altered form of hemoglobin that causes the production of non-functional red blood cells, no cure is presently available. The goal of this proposal is therefore to use our recent insight into the regulation of hemoglobin production to develop a new therapeutic strategy for the treatment of sickle cell disease. We know that hemoglobin, which is the major protein of the red blood cell, is vital because it transports oxygen from the lungs to all cells of the entire body. It is also known that two forms of hemoglobin exist, namely a fetal form, which is produced before birth and an adult form, which takes over around one year after birth. In sickle cell disease, only the adult form of hemoglobin is altered and this is the reason why patients with sickle cell disease are healthy prior to the switch from fetal to adult hemoglobin. Hence, preventing or reversing this switch may be lifesaving for sickle cell disease patients. When using mouse models carrying human hemoglobin genes, we found that a particular protein called "Gfi1b" can repress the fetal form of hemoglobin and that animals lacking Gfi1b still produce this fetal form of hemoglobin as adult animals. The present project will focus on this discovery and will ask the question whether the deletion of Gfi1b and the subsequent continuous production of fetal hemoglobin could be the basis for a curative therapy for sickle cell disease and even for another hemoglobinopathy thalassemia.

TRUDEL, Marie

Institut de recherches cliniques de Montreal

Canadian Blood Services-CIHR Partnership Operating Grant Program

Quebec

453132.0