Brain Gene therapy by sonoporation for Fragile X syndrome therapy – FUSBRAIN

Fragile X syndrome (FXS) is the most common cause of hereditary intellectual disability. At present, there is no treatment for this disease, only symptomatic treatments to reduce the effects of the disease are proposed. Gene therapy is a promising therapeutic strategy, however, an effective and non-invasive gene transfer method needs to be put in place. The use of ultrasound combined with gas microbubbles makes it possible to permeabilize the hemato-encephalic barrier transiently, thus favoring the targeted delivery of nucleic acids contained on the surface of these microbubbles. This method is called sonoporation. We have developed a platform for gene transfer into the brain by focused ultrasound using cationic microbubbles to transport plasmid DNA. In this project, we wish to evaluate the therapeutic effect of sonoporation on the Fragile X syndrome model. Modulation of the fine expression of FMRP is of strong interest for a restoration of the synaptic activity. For this, different plasmid vector and AAV will be developed to compare their efficiencies in the young mouse. An effective gene transfer protocol will be put in place and evaluated on the FMR1-KO model. The impact of FMRP expression in neurons and astrocytes and microglia will also be evaluated. A behavioral study will conclude on the cognitive and behavioral effects of different levels of re-expression of this protein.