Angubindin-1 opens the blood-brain barrier in vivo for delivery of antisense oligonucleotide to the central nervous system.

Angubindin-1 opens the blood-brain barrier in vivo for delivery of antisense oligonucleotide to the central nervous system.

Highlights

•Intravenously injected angubindin-1 attached to angulin-1 at the blood-brain barrier

•Subsequently administered antisense oligonucleotides were delivered into the brain

•The antisense oligonucleotides efficiently silenced the target RNA in the brain cells

•There were no overt adverse effects by angubindin-1 or antisense oligonucleotides

Abstract

Within the field of RNA therapeutics, antisense oligonucleotide-based therapeutics are a potentially powerful means of treating intractable diseases. However, if these therapeutics are used for the treatment of neurological disorders, safe yet efficient methods of delivering antisense oligonucleotides across the blood–brain barrier to the central nervous system must be developed. Here, we examined the use of angubindin-1, a binder to the tricellular tight junction, to modulate paracellular transport between brain microvascular endothelial cells in the blood–brain barrier for the delivery of antisense oligonucleotides to the central nervous system. This proof-of-concept study demonstrated that intravenously injected angubindin-1 increased the permeability of the blood–brain barrier and enabled transient delivery of subsequently administered antisense oligonucleotides into the mouse brain and spinal cord, leading to silencing of a target RNA without any overt adverse effects. We also found that two bicellular tight junction modulators did not produce such a silencing effect, suggesting that the tricellular tight junction is likely a better target for the delivery of antisense oligonucleotides than the bicellular tight junction. Our delivery strategy of modulating the tricellular tight junction in the blood–brain barrier via angubindin-1 provides a novel avenue of research for the development of antisense oligonucleotide-based therapeutics for the treatment of neurological disorders.

Journal Article

JOURNAL:
Journal of Controlled Release

TITLE:
Angubindin-1 opens the blood-brain barrier in vivo for delivery of antisense oligonucleotide to the central nervous system.

DOI:
https://doi.org/10.1016/j.jconrel.2018.05.010

Correspondence to

Takanori YOKOTA,M.D., Ph.D.,Professor
Department of Neurology and Neurological Science,
Graduate School of Medical and Dental Sciences,
Tokyo Medical and Dental University(TMDU)
E-mail:tak-yokota.nuro(at)tmd.ac.jp