Descripción del proyecto
Evaluación de terapias de edición del genoma para la anemia drepanocítica
La anemia drepanocítica es el resultado de la sustitución de un solo aminoácido de la cadena de betaglobina de la hemoglobina adulta. La gravedad de la anemia drepanocítica se ve atenuada por la co-herencia de mutaciones que activan la expresión de la gammaglobina fetal en los adultos. El trasplante de células madre/progenitoras hematopoyéticas (CMPH) autólogas modificadas genéticamente representa una opción terapéutica para la anemia drepanocítica. El equipo del proyecto EDITSCD, financiado con fondos europeos, se propone comprender los mecanismos moleculares y celulares que subyacen a las disfunciones de las CMPH en la anemia drepanocítica y evaluar la repercusión de los métodos de edición del genoma en dichas células. El objetivo del estudio es mejorar la estrategia de terapia génica de la anemia drepanocítica y evaluar las mejores herramientas y protocolos para las terapias de edición del genoma de las CMPH.
Objetivo
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 ActionsCoordinador
75015 Paris
Francia