期刊
MOLECULAR THERAPY-NUCLEIC ACIDS
卷 5, 期 -, 页码 -出版社
CELL PRESS
DOI: 10.1038/mtna.2016.69
关键词
amphiphilic conjugate; carrier-free transfection; 2 '-deoxy-2 '-fluoro-arabinonucleic acid (FANA); differentiated monolayer; intestinal disease therapy; nucleic acid delivery
资金
- Gebert Ruf Foundation [GRS-041/11]
- GRS-041/11), the Canadian Foundation for Health Research
- JSPS Strategic Young Researcher Overseas Visits Program for Accelerating Brain Circulation
Nucleic acid therapy can be beneficial for the local treatment of gastrointestinal diseases that currently lack appropriate treatments. Indeed, several oligonucleotides (ONs) are currently progressing through clinical trials as potential treatments for inflammatory bowel diseases. However, due to low uptake of carrier-free ONs by mucosal cells, strategies aimed at increasing the potency of orally administered ONs would be highly desirable. In this work, we explored the silencing properties of chemically modified and highly resistant ONs derivatized with hydrophobic alkyl chain on intestinal epithelial cells. We screened a set of lipid-ON conjugates for the silencing of model Bcl-2 mRNA and selected 2'-deoxy-2'-fluoro-arabinonucleic acid modified ON bearing docosanoyl moiety (L-FANA) as the most potent candidate with lowest toxicity. The efficacy of L-FANA conjugate was preserved in simulated intestinal fluids and in the inverted transfection setup. Importantly, L-FANA conjugate was able to downregulate target gene expression at both mRNA and protein levels in a difficult-to-transfect polarized epithelial cell monolayer in the absence of delivery devices and membrane disturbing agents. These findings indicate that lipid-ON conjugates could be promising therapeutics for the treatment of intestinal diseases as well as a valuable tool for the discovery of new therapeutic targets.
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