GLUT1 DEFICIENCY: NEW THERAPEUTIC STRATEGIES TO INCREASE GLUCOSE TRANSPORT ACROSS THE BLOOD BRAIN BARRIER (BBB)

The mammalian brain depends upon glucose as its main source of energy. However, glucose has only one single way to enter the brain, namely the Glut1 transporter present in the endothelium of brain capillaries. Brain endothelial cells form a tight Blood-Brain Barrier (BBB) that protects the brain from the ever-changing peripheral environment. BBB allows the passage of molecules from plasma to brain only across endothelial cells through specific transporters, while extracellular spaces in-between cells are sealed by tight junctions. Mutations in the gene encoding for Glut1 impair glucose transport to the brain, resulting in a severe neurological condition with seizures, intellectual disability and movement disorders. Since current treatments are largely ineffective, innovative therapies are on demand. Our main objective is to develop innovative tools to increase glucose transport across the BBB. We will follow two complementary strategies: (i) we will stimulate Glut1 synthesis by activating translation from the healthy copy of the Glut1 gene using non-coding RNAs; (ii) we will induce a transient BBB permeabilization using inhibitory peptides targeted to tight junctions to open the spaces between endothelial cells, letting glucose passively diffuse into the brain. To test these innovative molecular tools, we will develop a model of Glut1-deficient BBB using induced pluripotent stem cells obtained from Glut1-patients and differentiated in brain endothelium to mimic the patients' pathology. We expect to obtain a proof-of-concept of the ability of these strategies to rescue Glut1-deficiency in vitro, as a first step toward testing their therapeutic efficacy in vivo.