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

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.

Coordinator

IMAGINE INSTITUT DES MALADIES GENETIQUES NECKER ENFANTS MALADES FONDATION
Net EU contribution
€ 1 486 250,00
Address
24 Bd Du Montparnasse
75015 Paris 15
France

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Region
Ile-de-France Ile-de-France Paris
Activity type
Research Organisations
Non-EU contribution
€ 0,00

Participants (6)

OSPEDALE SAN RAFFAELE SRL
Italy
Net EU contribution
€ 1 000 000,00
Address
Via Olgettina 60
20132 Milano

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Region
Nord-Ovest Lombardia Milano
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
Non-EU contribution
€ 0,00
UNIVERSITAETSKLINIKUM FREIBURG
Germany
Net EU contribution
€ 1 330 000,00
Address
Hugstetter Strasse 49
79106 Freiburg

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Region
Baden-Württemberg Freiburg Freiburg im Breisgau, Stadtkreis
Activity type
Higher or Secondary Education Establishments
Non-EU contribution
€ 0,00
BAR ILAN UNIVERSITY
Israel
Net EU contribution
€ 610 000,00
Address
Bar Ilan University Campus
52900 Ramat Gan

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Activity type
Higher or Secondary Education Establishments
Non-EU contribution
€ 0,00
INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
France
Net EU contribution
€ 793 750,00
Address
Rue De Tolbiac 101
75654 Paris

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Region
Ile-de-France Ile-de-France Paris
Activity type
Research Organisations
Non-EU contribution
€ 0,00
ASTRAZENECA AB
Sweden
Net EU contribution
€ 520 000,00
Address
Vastra Maelarhamnen
151 85 Sodertaelje

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Region
Östra Sverige Stockholm Stockholms län
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
Non-EU contribution
€ 0,00
EATRIS ERIC
Netherlands
Net EU contribution
€ 261 250,00
Address
De Boelelaan 1118
1081 HZ Amsterdam

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Region
West-Nederland Noord-Holland Groot-Amsterdam
Activity type
Research Organisations
Non-EU contribution
€ 0,00