Novel lentiviral vectors for gene therapy of sickle cell disease combining gene addition and gene silencing strategies

Sickle cell disease (SCD) is due to a mutation in the O-globin gene causing production of the toxic sickle hemoglobin (HbS; ex2OS2). Transplantation of autologous hematopoietic stem and progenitor cells (HSPCs) transduced with lentiviral vectors (LVs) expressing an anti-sickling O-globin (OAS) is a promising treatment; however, it is only partially effective, and patients still present elevated HbS levels. Here, we developed a bifunctional LV expressing OAS3-globin and an artificial microRNA (amiRNA) specifically downregulating OS-globin expression with the aim of reducing HbS levels and favoring OAS3 incorporation into Hb tetramers. Efficient transduction of SCD HSPCs by the bifunctional LV led to a substantial decrease of OS-globin transcripts in HSPC-derived erythroid cells, a significant reduction of HbS+ red cells, and effective correction of the sickling phenotype, outperforming OAS gene addition and BCL11A gene silencing strategies. The bifunctional LV showed a standard integration profile, and neither HSPC viability, engraftment, and multilineage differentiation nor the erythroid transcriptome and miRNAome were affected by the treatment, confirming the safety of this therapeutic strategy. In conclusion, the combination of gene addition and gene silencing strategies can improve the efficacy of current LV-based therapeutic approaches without increasing the mutagenic vector load, thus representing a novel treatment for SCD

Vers l’hypothèse d’une identité de déplacement: congruence entre espaces social, cognitif et géographique

info:eu-repo/semantics/nonPublishe

Type Theories and Lexical Networks : using Serious Games as the basis for Multi-Sorted Typed Systems

In this paper, we show how a rich lexico-semantic network which Has been built using serious games, JeuxDeMots, can help us in grounding our semantic ontologies in doing formal semantics using rich or modern type theories (type theories within the tradition of Martin Löf). We discuss the issue of base types, adjectival and verbal types, hyperonymy/hyponymy relations as well as more advanced issues like homophony and polysemy. We show how one can take advantage of this wealth of lexical semantics in a formal compositional semantics framework. We argue that this is a way to sidestep the problem of deciding what the type ontology should look like once a move to a many sorted type system has been made. Furthermore, we show how this kind of information can be extracted from a lexico-semantic Network like JeuxDeMots and inserted into a proof-assistant like Coq in order to perform reasoning tasks

Vers l'hypothèse d'une identité de déplacement. Congruence entre espace social, cognitif et géographique

info:eu-repo/semantics/publishe

Les mobilités quotidiennes: représentations et pratiques. Vers l'identité de déplacement

41799info:eu-repo/semantics/publishe

Les mobilités quotidiennes : Représentation et pratiques. Vers l'identité de déplacement

Rapport final du programme ATIP CNRS Jeunes Chercheurs 200

Les mobilités quotidiennes : Représentation et pratiques. Vers l'identité de déplacement

Rapport final du programme ATIP CNRS Jeunes Chercheurs 200