Descrizione del progetto
Valutazione delle terapie di editing genomico per l’anemia falciforme
L’anemia falciforme (SCD, Sickle cell disease) è il risultato di una sostituzione di un singolo amminoacido nella catena beta-globinica dell’emoglobina degli adulti. La gravità della SCD è attenuata dalla coereditarietà delle mutazioni che determinano l’espressione della gamma-globina fetale negli adulti. Il trapianto di cellule staminali/progenitrici ematopoietiche autologhe, geneticamente modificate, rappresenta un’opzione terapeutica per la SCD. Il progetto EDITSCD, finanziato dall’UE, si propone di comprendere i meccanismi molecolari e cellulari alla base delle disfunzioni delle cellule staminali/progenitrici ematopoietiche SCD e di valutare l’impatto degli approcci di editing del genoma sulle cellule staminali/progenitrici ematopoietiche SCD. L’obiettivo dello studio è quello di migliorare la strategia di terapia genica della SCD e di valutare i migliori strumenti e protocolli per le terapie di editing genomico delle cellule staminali/progenitrici ematopoietiche.
Obiettivo
Sickle cell disease (SCD) is one of the most prevalent monogenic diseases in Europe. A single amino acid substitution in the beta-globin chain of the adult hemoglobin (Hb) drives red blood cell sickling and multi-organ damage. The clinical severity of SCD 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 hematopoietic stem/progenitor cells (HSPCs) is an attractive therapeutic option for SCD patients. To this end, genome editing approaches based on the use of site-specific nucleases or, more recently, base editors have been explored by many groups, including teams in our consortium. These approaches either correct the single point mutation causing SCD or reactivate fetal gamma-globin expression by mimicking HPFH mutations. On the other hand, (pre)clinical data from SCD patients or SCD mouse models, as well as preliminary data from our labs suggest that SCD HSPCs are characterized by a high mutational burden, oxidative stress and expression of inflammatory genes. This can alter HSPC properties as well as their interactions within the bone marrow niche. In the context of gene therapy, it is essential to understand the mechanisms underlying SCD HSPC dysfunction and assess the impact of genome editing approaches on SCD HSPCs. In this proposal, we have assembled a multidisciplinary team to: (i) understand the molecular and cellular mechanisms underlying SCD HSPC autonomous and non-cell-autonomous dysfunctions and (ii) evaluate the impact of established and novel genome editing approaches on SCD HSPC properties and genome integrity. This study will lay the foundation of an improved gene therapy strategy to treat SCD and provide best practice tools and protocols for genome editing-based therapies in HSPCs.
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HORIZON-RIA - HORIZON Research and Innovation ActionsCoordinatore
75015 Paris
Francia