DBAGenCure: Lentiviral-mediated gene therapy for Diamond Blackfan Anemia: Preclinical Safety and Efficacy Studies

Diamond-Blackfan Anemia (DBA) is an inherited bone marrow failure (IBMF) syndrome mainly characterized by red cell aplasia, congenital anomalies and increased risk of cancer. The annual incidence of DBA is 5 per million life births. So far, mutations in 20 DBA genes have been identified, although mutations in RPS19 are the most frequent (25%). Hematopoietic stem cell transplantation (HSCT) from familiar or fully matched (10/10) unrelated donors is indicated in transfusion-dependent patients, but many patients lack a suitable donor, and the output of HSCTs from alternative donors is still poor. Based on the encouraging results obtained by members of this Consortium in an ongoing gene therapy trial in another IBMF syndrome (Fanconi anemia, FA), now we aim at developing the preclinical studies required for a subsequent gene therapy trial in DBA patients with mutations in RPS19. We have already developed two lentiviral vectors capable of reverting the phenotype of DBA hematopoietic progenitor cells in vitro. In this proposal, in vitro and also in vivo experimental studies will be conducted to demonstrate the efficacy of a gene therapy approach to correct both the ribosomal biogenesis and erythropoietic defects characteristics of DBA. In parallel, bio-distribution, toxicity and proviral insertion site studies will be performed according to EMA guidelines. Studies conducted will allow us to apply for an Orphan Drug Designation both at EMA and FDA, aiming at developing a gene therapy trial in RPS19-DBA patients to prevent and/or rescue the BMF characteristic of the disease.