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Assessing efficacy and safety of genome EDITing approaches for Sickle Cell Disease

Project description

Evaluation of genome-editing therapies for sickle cell disease

Sickle cell disease (SCD) is a result of a single amino acid substitution in the beta-globin chain of adult haemoglobin. The severity of SCD is alleviated by the co-inheritance of mutations driving the expression of foetal gamma-globin in adults. Transplantation of autologous, genetically modified haematopoietic stem/progenitor cells (HSPC) represents a therapeutic option for SCD. The EU-funded EDITSCD project aims to understand the molecular and cellular mechanisms underlying SCD HSPC dysfunctions and evaluate the impact of genome editing approaches on SCD HSPC. The study objective is to improve the SCD gene therapy strategy and evaluate the best tools and protocols for genome editing HSPC therapies.

Objective

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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Coordinator

IMAGINE INSTITUT DES MALADIES GENETIQUES NECKER ENFANTS MALADES FONDATION
Net EU contribution
€ 1 486 250,00
Address
24 bd du montparnasse
75015 Paris
France

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Region
Ile-de-France Ile-de-France Paris
Activity type
Research Organisations
Links
Other funding
€ 0,00

Participants (6)

Partners (1)