Modulation of blood-brain barrier function by a heteroduplex oligonucleotide in vivo
Hiroya Kuwahara, Takanori Yokota Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University
The blood-brain barrier (BBB) is no longer regarded only as a substantial barrier for drug delivery to the brain, but also as a dynamic interface that adapts to the needs of the brain and responds to physiological changes; the BBB is affected by and can even promote diseases. To expand our understanding of how the BBB functions and interacts with its environment, it is important to establish a platform technology to be able to control gene expression in brain microvascular endothelial cells (BMECs), which are core components of the BBB, in vivo. Moreover, the ability to manipulate pathological molecules in BMECs can lead to the development of a new class of molecular targeted therapy for a variety of intractable neurological disorders such as multiple sclerosis, Alzheimer's disease, and stroke. We recently developed a new “heteroduplex oligonucleotide” (HDO) approach that achieves highly efficient gene silencing in vivo. HDO is composed of an ASO as the parent strand, having a gapmer structure (DNA nucleotides franked by a few locked nucleic acid (LNA) nucleotides), duplexed with the complementary RNA (cRNA). The intravenously administered α-tocopherol-conjugated HDO (Toc-HDO), in which α-tocopherol (a delivery ligand) is covalently conjugated to the 5′-end of the cRNA, binds to serum lipoproteins in blood circulation, and is distributed along the physiological transport pathway of α-tocopherol. Here we show that our HDO conjugated to α-tocopherol as a delivery ligand, efficiently reduced the expression of organic anion transporter 3 (OAT3) gene in brain microvascular endothelial cells in mice. This proof-of-concept study demonstrates that intravenous administration of chemically synthesized HDO can remarkably silence OAT3 at the mRNA and protein levels. We also demonstrated modulation of the efflux transport function of OAT3 at the BBB in vivo. HDO will serve as a novel platform technology to advance the biology and pathophysiology of the BBB in vivo, and will also open a new therapeutic field of gene silencing at the BBB for the treatment of various intractable neurological disorders.
Nishina, K. et al. DNA/RNA heteroduplex oligonucleotide for highly efficient gene silencing. Nat. Commun. 6, 7969 (2015)
Kuwahara, H. et al. Modulation of blood-brain barrier function by a heteroduplex oligonucleotide in vivo. Sci. Rep. 8, 4377 (2018)
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