Crossing the blood–brain-barrier with viral vectors

• Abundant vasculature could provide access to the CNS but is blocked by the BBB.
• Disruption of BBB tight junctions allows paracellular transport of viral vectors.
• Transient BBB disruption can be global or local.
• Receptor-mediated transcytosis transports viral vectors across the intact BBB.
• Directed evolution can greatly enhance vector transcytosis across BBB.

The abundant vasculature of the CNS provides a compelling route of administration for the delivery of gene therapy vectors if the limitations imposed by the blood–brain-barrier (BBB) can be overcome. There are two general approaches to transporting viral vectors across the BBB: either by transient disruption of brain microvasculature endothelial tight junctions, or through the use of receptor-mediated transcytosis. Advances in BBB disruption have led to pre-clinical success for both global and localized gene delivery, while therapies based on receptor-mediated transcytosis have recently advanced to phase I clinical trials in humans. Both approaches show long term promise for treating a wide range of CNS diseases.