Abstract: The present invention relates to variants of lysosomal acid lipase (LAL) and uses thereof.

Abstract: Gene therapy of SCO is based on the transplantation of genetically modified HSCs. Several LV approaches based on gene addition consist in transducing patient HSCs with a lentiviral vector expressing an anti-sickling ?-like globin chain such as use of ?AS3 HBB anti-sickling variants. Here, the inventors have improved the design of the LV-AS3 vector to treat SCO patients. These LVs allow the simultaneous expression of the potent anti-sickling ?AS3-globin and an artificial miR (amiR) silencing the ?S-globin. The reduction of ?S-globin levels will increase the incorporation of ?AS3-globin in Hb tetramers, which should increase the proportion of corrected RBCs in SCO patients. The inventors selected the best-performing miRs, and modified the therapeutic ?AS3-globin transgene by inserting silent mutations to avoid the recognition by the amiR and the silencing of the transgene.

Abstract: The invention relates to a composition for enhancing utrophin expression in cell by inducing mutations within a target sequence comprising a utrophin repressor binding site using a gene editing enzyme and the use thereof for the treatment of a dy-strophinopathy.

Abstract: The present invention relates to a genetically modified hematopoietic stem cell (HSC) comprising, in at least one ?-globin gene comprised in the genome thereof, at least one transgene encoding a functional ?-like globin protein, the said transgene being placed under the control of the endogenous promoter of the said at least one ?-globin gene.

Abstract: The #?-hemoglobinopathies #?-thalassemia (BT) and sickle cell disease (SCD) are the most frequent genetic disorders worldwide. These diseases are caused by mutations causing reduced or abnormal synthesis of the ?-globin chain of the adult hemoglobin (Hb) tetramer. Here, the inventors intend to improve HSC-based gene therapy for ?-thalassemia and SCD by developing an innovative, highly infectious LV vector expressing a potent anti-sickling ?-globin transgene and a second biological function either increasing fetal ?-globin expression (for ?-thalassemia and SCD). More particularly, the inventors have designed a novel lentivirus (LV), which carry two different functions: ?AS3 gene addition and gene silencing. This last strategy allows the re-expression of the fetal ?-globin genes (HBG1 and HBG2) and production of the endogenous fetal hemoglobin (HbF).

Abstract: IPEX (Immune dysregulation Polyendocinopathy X linked) syndrome is a primary immunodeficience caused by mutations in the gene encoding the transcription factor forkhead box P3 (FOXP3), which leads to the loss of function of thymus-derived CD4+CD25+ regulatory T (tTreg) cells. Preclinical and clinical studies suggest that T cell gene therapy approaches designed to selectively restore the repertoire of Treg cells by transfer of wild type FOXP3 gene is a promising potential cure for IPEX. However, there is still a need for a vector that can be used efficiently for the preparation of said Treg cells. The inventors thus compared 6 different lentiviral constructs according to 4 criteria (vector titers, level of transduction of human CD4+ T cells, level of expression of FOXP3 and ?LNGFR genes, degree of correlation between both expression) and selected one construct comprising a bidirectional EFS-PGK promoter that showed remarkable efficiency.

Abstract: IPEX (Immune dysregulation Polyendocrinopathy X linked) syndrome is a primary immunodeficiency caused by mutations in the gene encoding the transcription factor forkhead box P3 (FOXP3), which leads to the loss of function of thymus-derived CD4+CD25+ regulatory T (tTreg) cells. Preclinical and clinical studies suggest that T cell gene therapy approaches designed to selectively restore the repertoire of Treg cells by transfer of wild type FOXP3 gene is a promising potential cure for IPEX. However, there is still a need for a vector that can be used efficiently for the preparation of said Treg cells. The inventors thus compared 6 different lentiviral constructs according to 4 criteria (vector titers, level of transduction of human CD4+ T cells, level of expression of FOXP3 and ?LNGFR genes, degree of correlation between both expression) and selected one construct comprising a bidirectional PGK-EF1a promoter that showed remarkable efficiency.

Abstract: The present invention relates to a genetically modified hematopoietic stem cell comprising, in at least one globin gene comprised in the genome thereof, at least one transgene encoding a therapeutic protein or a therapeutic ribonucleic acid, the said transgene being placed under the control of the endogenous promoter of the said globin gene.

Abstract: It is described a bidirectional promoter for expression of at least two coding sequences in opposite direction in animal cells; bidirectional expression cassettes; expression constructs; gene transfer expression vectors, and methods for the use thereof.

Abstract: It is described a bidirectional promoter for expression of at least two coding sequences in opposite direction in animal cells; bidirectional expression cassettes; expression constructs; gene transfer expression vectors, and methods for the use thereof.