A novel and translational role for autophagy in antisense oligonucleotide trafficking and activity.

Autor:	Ochaba J; Ionis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA., Powers AF; Ionis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA., Tremble KA; Ionis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA., Greenlee S; Ionis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA., Post NM; Ionis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA., Matson JE; Ionis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA., MacLeod AR; Ionis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA., Guo S; Ionis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA., Aghajan M; Ionis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA.
Jazyk:	angličtina
Zdroj:	Nucleic acids research [Nucleic Acids Res] 2019 Dec 02; Vol. 47 (21), pp. 11284-11303.
DOI:	10.1093/nar/gkz901
Abstrakt:	Endocytosis is a mechanism by which cells sense their environment and internalize various nutrients, growth factors and signaling molecules. This process initiates at the plasma membrane, converges with autophagy, and terminates at the lysosome. It is well-established that cellular uptake of antisense oligonucleotides (ASOs) proceeds through the endocytic pathway; however, only a small fraction escapes endosomal trafficking while the majority are rendered inactive in the lysosome. Since these pathways converge and share common molecular machinery, it is unclear if autophagy-related trafficking participates in ASO uptake or whether modulation of autophagy affects ASO activity and localization. To address these questions, we investigated the effects of autophagy modulation on ASO activity in cells and mice. We found that enhancing autophagy through small-molecule mTOR inhibition, serum-starvation/fasting, and ketogenic diet, increased ASO-mediated target reduction in vitro and in vivo. Additionally, autophagy activation enhanced the localization of ASOs into autophagosomes without altering intracellular concentrations or trafficking to other compartments. These results support a novel role for autophagy and the autophagosome as a previously unidentified compartment that participates in and contributes to enhanced ASO activity. Further, we demonstrate non-chemical methods to enhance autophagy and subsequent ASO activity using translatable approaches such as fasting or ketogenic diet. (© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.)
Databáze:	MEDLINE
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