“Endothelial antibody factory” at the Blood Brain Barrier: novel approach to therapy of neurodegenerative diseases

Abstract Phase III clinical trials of immunotherapies against Alzheimer’s disease have failed to hit major endpoints. Despite the high doses administered, small fractions of injected monoclonal antibodies cross the blood brain barrier (BBB), likely resulting in an antibody concentration in the brain parenchyma that is too low for a therapeutic effect. Here we report a novel approach to circumvent this obstacle. Leveraging the homing properties of endothelial progenitor cells (EPCs) to reach impaired BBB, we transfected ex vivo EPCs with vectors encoding anti-β-amyloid and anti-TDP-43 antibody fragments (Fabs). The expressed Fabs retained the ability to bind to, and extensively solubilize, β-amyloid and TDP-43 aggregates. Immunofluorescence studies showed that when injected into mice, the transfected EPCs homed to the BBB where they adhered, integrated, and expressed Fabs which localized in the brain parenchyma and perivascular space. This approach can be optimized and developed as a possible cell-based gene and immunotherapy.