Innovating Works

DITSB

Financiado
Development of Innovative Therapeutic Strategies for beta hemoglobinopathies
Beta-thalassemia and sickle cell disease (SCD) are caused by mutations affecting the synthesis or the structure of the adult hemoglobin (Hb) beta-chain. The only definitive cure is transplantation of allogeneic hematopoietic stem... Beta-thalassemia and sickle cell disease (SCD) are caused by mutations affecting the synthesis or the structure of the adult hemoglobin (Hb) beta-chain. The only definitive cure is transplantation of allogeneic hematopoietic stem cells (HSCs) from an HLA-matched donor, an option available to <30% of the patients. The clinical severity of beta-hemoglobinopathies is alleviated by the co-inheritance of mutations causing expression of fetal gamma-globin in adult life - a condition termed hereditary persistence of fetal hemoglobin (HPFH). Transplantation of autologous, genetically modified HSCs is an attractive therapeutic option for patients lacking a suitable donor. To this aim, genome editing approaches based on the use of site-specific nucleases have been explored by many groups, including ours. These approaches may either revert the single point mutation causing SCD or reactivate fetal globin expression, by mimicking HPFH mutations or by decreasing the level of BCL11A, a master repressor of fetal Hb synthesis. Site-specific nucleases, however, generate double-strand breaks (DSBs) in the genome and raise safety concerns for clinical applications, particularly when used in DSB-sensitive HSCs. In this proposal, we aim at exploiting targeted base-editing to develop novel, efficacious and safe strategies for beta-hemoglobinopathies without generating DSBs. This will be attempted by (i) correcting the SCD-causing mutation, (ii) mimicking HPFH mutations in the gamma-globin promoters, or (iii) modulating the activity of a BCL11A erythroid-specific enhancer. These approaches will be tested in human adult erythroid cell lines and patient HSCs, differentiated in vitro and in vivo into mature red cells to evaluate editing efficiency, fetal Hb expression, phenotypic cell correction and biosafety. The ultimate goal of the project is to provide sufficient proof of efficacy and safety to enable the clinical development of base-edited HSCs for the therapy of beta-hemoglobinopathies. ver más
31/05/2025
INSERM
2M€
Duración del proyecto: 62 meses Fecha Inicio: 2020-03-24
Fecha Fin: 2025-05-31

Línea de financiación: concedida

El organismo H2020 notifico la concesión del proyecto el día 2020-03-24
Línea de financiación objetivo El proyecto se financió a través de la siguiente ayuda:
ERC-2019-COG: ERC Consolidator Grant
Cerrada hace 5 años
Presupuesto El presupuesto total del proyecto asciende a 2M€
Líder del proyecto
INSTITUT NATIONAL DE LA SANTE ET DE LA RECHER... No se ha especificado una descripción o un objeto social para esta compañía.
Perfil tecnológico TRL 4-5