RRC ID |
47963
|
著者 |
Donner AJ, Wancewicz EV, Murray HM, Greenlee S, Post N, Bell M, Lima WF, Swayze EE, Seth PP.
|
タイトル |
Co-Administration of an Excipient Oligonucleotide Helps Delineate Pathways of Productive and Nonproductive Uptake of Phosphorothioate Antisense Oligonucleotides in the Liver.
|
ジャーナル |
Nucleic Acid Ther
|
Abstract |
Phosphorothioate (PS) modified antisense oligonucleotides (ASOs) have progressed rapidly in the clinic for treating a variety of disease indications. We previously demonstrated that the activity of PS ASOs in the liver can be enhanced by co-infusion of an excipient oligonucleotide (EON). It was posited that the EON saturates a nonproductive uptake pathway(s) thereby permitting accumulation of the PS ASO in a productive tissue compartment. In this report, we measured PS ASO activity following administration by bolus, infusion or co-fusion with EON within hepatocytes and nonparenchymal cells (NPCs), of the liver. This revealed that while ASOs accumulate preferentially in NPCs, they are intrinsically more active in hepatocytes. Furthermore, we show that the EON enhances ASO potency when infused up to 72 h before or after administration of the active ASO suggesting that the EON can saturate and displace the ASO from nonproductive to productive compartments. Physical presence of the EON in tissues was required for optimal potentiation suggesting that there is a dynamic distribution of the ASO and EON between the compartments. Lastly, using a candidate approach, we confirmed Stabilin-2 as a molecular pathway for ASO uptake in sinusoidal endothelial cells and the ASGR as a pathway for ASO uptake into hepatocytes in the liver.
|
巻・号 |
27(4)
|
ページ |
209-220
|
公開日 |
2017-8-1
|
DOI |
10.1089/nat.2017.0662
|
PMID |
28448194
|
MeSH |
Animals
Cell Adhesion Molecules, Neuronal / metabolism
Cell Line, Tumor
Coculture Techniques
Endothelial Cells / metabolism
Excipients / administration & dosage
Excipients / pharmacokinetics*
Hepatocytes / drug effects
Hepatocytes / metabolism
Liver / cytology
Liver / metabolism*
Male
Mice, Inbred BALB C
Mice, Inbred C57BL
Oligonucleotides, Antisense / administration & dosage
Oligonucleotides, Antisense / pharmacokinetics*
Phosphorothioate Oligonucleotides / administration & dosage
Phosphorothioate Oligonucleotides / pharmacokinetics*
Tissue Distribution
|
IF |
5.0
|
引用数 |
9
|
リソース情報 |
実験動物マウス |
RBRC02796 |