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Auteur / Autrice : Thomas Moreau
Direction : Cécile Tonnelle
Type : Thèse de doctorat
Discipline(s) : Pathologie humaine. Oncologie
Date : Soutenance en 2006
Etablissement(s) : Aix-Marseille 2

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Résumé

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X-linked agammaglobulinemia (XLA), or Bruton’s disease, is the most common human primar humoral immunodeficiency. XLA is caused by mutations of the Bruton’s tyrosine kinase (BTK), that lead to an arrest in early B cell differentiation with lack of mature peripheral B cells and low levels of serum immunoglobulins. Affected males develop recurrent bacterial and enteroviral infections. Btk is normally expressed in all hematopoietic lineages except Tlymphocytes and plasma cells, and is critical for B cell development. We rationally defined a minimal promoter derived from the human CD19 gene regulatory regions using a bio-informatics approach and validated a lentiviral vector containing a 1274bp regulatory sequence able to restrict transgene expression to the B-cell progeny of genetically modified CD34+ hematopoietic progenitors through long term in vivo differentiation ( Mol. Ther. 2004;10:45-56). Addition to the CD19 promoter of the EEmar sequence, from the enhancer of the murine immunoglobulin heavy chain gene, improved transgene expression while retaining B-cell specificity in a second generation lentiviral vector. BTK transgene is preferentially expressed in B-lymphoid cell lines and in B-lymphocytes differentiated from transduced CD34+ cord blood or bone marrow progenitors. This B-specific lentiviral vector represents an attractive tool for gene therapy applications targeting hereditary diseases affecting B cell lineage such as XLA.