Transvascular Delivery of Hydrophobically Modified siRNAs: Gene Silencing in the Rat Brain upon Disruption of the Blood-Brain Barrier

Molecular Therapy : the Journal of the American Society of Gene Therapy
Bruno Mdc GodinhoAnastasia Khvorova

Abstract

Effective transvascular delivery of therapeutic oligonucleotides to the brain presents a major hurdle to the development of gene silencing technologies for treatment of genetically defined neurological disorders. Distribution to the brain after systemic administrations is hampered by the low permeability of the blood-brain barrier (BBB) and the rapid clearance kinetics of these drugs from the blood. Here we show that transient osmotic disruption of the BBB enables transvascular delivery of hydrophobically modified small interfering RNA (hsiRNA) to the rat brain. Intracarotid administration of 25% mannitol and hsiRNA conjugated to phosphocholine-docosahexanoic acid (PC-DHA) resulted in broad ipsilateral distribution of PC-DHA-hsiRNAs in the brain. PC-DHA conjugation enables hsiRNA retention in the parenchyma proximal to the brain vasculature and enabled active internalization by neurons and astrocytes. Moreover, transvascular delivery of PC-DHA-hsiRNAs effected Htt mRNA silencing in the striatum (55%), hippocampus (51%), somatosensory cortex (52%), motor cortex (37%), and thalamus (33%) 1 week after administration. Aside from mild gliosis induced by osmotic disruption of the BBB, transvascular delivery of PC-DHA-hsiRNAs was not ...Continue Reading

Citations

Dec 14, 2018·Pharmaceutics·Daniel Mihai TeleanuRaluca Ioana Teleanu
Jun 22, 2021·Current Drug Delivery·Sumel AshiquePooja A Chawla
Nov 28, 2021·Pharmaceutics·Rory WhelanAndrew J S Knox
Dec 5, 2021·AAPS PharmSciTech·Nkafu Bechem NdemazieEdward Agyare

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