Editors' ChoiceDrug Delivery

Linked in: Cholesterol connects oligos to liver

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Science Translational Medicine  17 Feb 2016:
Vol. 8, Issue 326, pp. 326ec27
DOI: 10.1126/scitranslmed.aaf3848

Targeting liver cells, called hepatocytes, with antisense oligonucleotides (ASOs) could allow for the modulation of genes that control cholesterol flux. Because cholesterol naturally travels through the liver, it can be hitched to therapeutic ASOs needing a ride there. Wada and colleagues report the development and characterization of a new set of linkers that connect cholesterol to ASOs, enabling hepatocyte localization and specific knockdown of Pcsk9—a gene that, when suppressed, allows greater uptake of low-density lipoprotein (LDL) in the liver and, thus, reduces circulating levels of “bad” cholesterol. The investigators evaluated a series of linkers for 3ʹ and 5ʹ cholesterol conjugation, including the hydrophobic molecule hexamethylene succinimide (HMS) and the hydrophilic triethyleneglycol (TEG). They also incorporated disulfide-containing moieties for easy cleavage by intracellular glutathione. In mice, 3ʹ cholesterol-conjugated ASOs generally demonstrated greater hepatic localization, with the TEG-conjugated version demonstrating a 60% reduction in Pcsk9 mRNA. Similar knockdown efficiencies were noted when 3ʹ-cholesterol-TEG ASO targeted ApoB. The 3ʹ-cholesterol-HMS-conjugated ASO also localized in hepatocytes but was less effective in knocking down target mRNA, thus supporting the role of the linkers in modulating cellular tropism and gene targeting. The authors did not yet test in disease models, but it is clear that, with the right linker to therapeutic ASOs, good cholesterol can hit the spot, safely and with good efficiency.

S. Wada et al., Evaluation of the effects of chemically different linkers on hepatic accumulations, cell tropism and gene silencing ability of cholesterol-conjugated antisense oligonucleotides. J. Control. Release 10.1016/j.jconrel.2016.02.007 (2016). [Abstract]

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