論文 - 詳細
| 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 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
|
| 最多言及媒体 | Patent(IFI CLAIMS) |
| 各媒体での言及数の合計 | 8 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 実験動物マウス | RBRC02796 |