Vesicular Glutamate Transporters in Astrocytes as Potential New Therapeutic Targets: Astrocyte-targeted Viral Vectors Expressing Inhibitory Nanobodies

Abstract

Astrocytes, the main Central Nervous System (CNS) glial cell type, actively release transmitters, including glutamate, and thereby participate in physiological brain information processing. However, dysregulated transmitter release from astrocytes can contribute to CNS disease pathogenesis and progression. Therefore, targeting astrocyte glutamate release is a promising new therapeutic strategy in hyper-glutamatergic brain conditions, as it does not directly block glutamatergic neurotransmission. Basing on the evidence that astrocytes express Vesicular Glutamate Transporters (VGLUT), in collaboration with other NCCR TransCure partners, we developed an innovative approach for astrocyte-selective delivery of nanobodies inhibiting VGLUT. We inserted the anti-VGLUT nanobody constructs in astrocyte-directed viral vectors that were administered peripherally, crossed the blood-brain-barrier and led to successful cell-specific CNS-wide expression of the nanobodies.