Targeted delivery of antisense oligonucleotides to pancreatic β-cells

被引：135

作者：

Ammala, C. ^{[1
]}

Drury, W. J., III ^{[1
]}

Knerr, L. ^{[1
]}

Ahlstedt, I ^{[1
]}

Stillemark-Billton, P. ^{[1
]}

Wennberg-Huldt, C. ^{[1
]}

Andersson, E-M ^{[1
]}

Valeur, E. ^{[1
]}

Jansson-Lofmark, R. ^{[1
]}

Janzen, D. ^{[1
]}

Sundstrom, L. ^{[2
]}

Meuller, J. ^{[2
]}

Claesson, J. ^{[2
]}

Andersson, P. ^{[3
]}

Johansson, C. ^{[3
]}

Lee, R. G. ^{[4
]}

Prakash, T. P. ^{[4
]}

Seth, P. P. ^{[4
]}

Monia, B. P. ^{[4
]}

Andersson, S. ^{[1
]}

机构：

[1] AstraZeneca, IMED Biotech Unit, Cardiovasc Renal & Metab Dis, Gothenburg, Sweden

[2] AstraZeneca, IMED Biotech Unit, Discovery Sci, Gothenburg, Sweden

[3] AstraZeneca, IMED Biotech Unit, Drug Safety & Metab, Gothenburg, Sweden

[4] Ionis Pharmaceut, 2855 Gazelle Court, Carlsbad, CA 92010 USA

来源：

SCIENCE ADVANCES | 2018年 / 4卷 / 10期

关键词：

PEPTIDE-1; RECEPTOR; TRAFFICKING; GLP-1; HEPATOCYTES; TYPE-2; ENDOCYTOSIS; THERAPIES; LIVER; MICE;

D O I：

10.1126/sciadv.aat3386

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Antisense oligonucleotide (ASO) silencing of the expression of disease-associated genes is an attractive novel therapeutic approach, but treatments are limited by the ability to deliver ASOs to cells and tissues. Following systemic administration, ASOs preferentially accumulate in liver and kidney. Among the cell types refractory to ASO uptake is the pancreatic insulin-secreting beta-cell. Here, we show that conjugation of ASOs to a ligand of the glucagon-like peptide-1 receptor (GLP1R) can productively deliver ASO cargo to pancreatic beta-cells both in vitro and in vivo. Ligand-conjugated ASOs silenced target genes in pancreatic islets at doses that did not affect target gene expression in liver or other tissues, indicating enhanced tissue and cell type specificity. This finding has potential to broaden the use of ASO technology, opening up novel therapeutic opportunities, and presents an innovative approach for targeted delivery of ASOs to additional cell types.

引用

页数：11

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