VALIDATION OF THE HUMAN DELTA GLOBIN GENE AS A THERAPEUTIC TARGET FOR BETA THALASSEMIA AND SICKLE CELL DISEASE

The aim of the research

Main researcher MARIA SERAFINA RISTALDI

β-thalassemia and SCD are widespread diseases and a global health problem.

The incidence of β-thal. and SCD has in recent years significantly increased in Italy due to migration.There is no available definitive cure with the exception of bone marrow transplantation, possible only for a minority of patients. Is thus necessary to find alternative ways to treat the disease. The experimental alternatives are gene therapy or reactivation of the endogenous γ-globin gene but so far with limited success. Studies in vitro and in vivo by our group lead us to believe that the human δ globin gene activation could represent a valid alternative to the treatment of β-hemoglobinopathies. We have previously demonstrated in vivo the possibility to activate the human δ globin gene by the creation of a consensus sequence for the transcription factor EKLF. The activation obtained is theoretically sufficient to compensate the imbalance of globin chains in β-thal. and to act as an antisckling agent in SCD. Based on these results we have undertaken studies in vivo, our data confirm that it is possible to activate the δ globin gene at a level which is therapeutic in a mice model of β-thalassemia intermedia (Manchinu 2014) and potentially therapeutic for the β-thal. major and SCD. We aim to validate the human δ globin gene as a therapeutic target alternative to the fetal γ globin gene reactivation or "classical " gene therapy for the treatment of β-hemoglobinopathies. To this end we have created a transgenic mouse with a high δ globin gene expression. We will attempt to rescue a β-thal. Major and SCD mice models In addition we will create fetal liver cell lines derived from a dual reporter transgenic mouse to be used for screening of small molecules for a possible clinical use The ultimate goal of this study is the possible application on the patients with the improvement of their life condition and expectancy by the use of molecules that may burst the δ globin gene expression.