Bibliographic Details
| Title: |
Chloroquine and cytosolic galectins affect endosomal escape of antisense oligonucleotides after Stabilin-mediated endocytosis |
| Authors: |
Ekta Pandey, Edward N. Harris |
| Source: |
Molecular Therapy: Nucleic Acids, Vol 33, Iss , Pp 430-443 (2023) |
| Publisher Information: |
Elsevier, 2023. |
| Publication Year: |
2023 |
| Collection: |
LCC:Therapeutics. Pharmacology |
| Subject Terms: |
MT: Delivery Strategies, Stabilin, endosome escape, endocytosis, antisense oligonucleotide, galectin, Therapeutics. Pharmacology, RM1-950 |
| More Details: |
Non-DNA-binding Stabilin-2/HARE receptors expressed on liver sinusoidal endothelial cells specifically bind to and internalize several classes of phosphorothioate antisense oligonucleotides (PS-ASOs). After Stabilin-mediated uptake, PS-ASOs are trafficked within endosomes (>97%–99%), ultimately resulting in destruction in the lysosome. The ASO entrapment in endosomes lowers therapeutic efficacy, thereby increasing the overall dose for patients. Here, we use confocal microscopy to characterize the intracellular route transverse by PS-ASOs after Stabilin receptor-mediated uptake in stable recombinant Stabilin-1 and -2 cell lines. We found that PS-ASOs as well as the Stabilin-2 receptor transverse the classic path: clathrin-coated vesicle-early endosome-late endosome-lysosome. Chloroquine exposure facilitated endosomal escape of PS-ASOs leading to target knockdown by more than 50% as compared to untreated cells, resulting in increased PS-ASO efficacy. We also characterize cytosolic galectins as novel contributor for PS-ASO escape. Galectins knockdown enhances ASO efficacy by more than 60% by modulating EEA1, Rab5C, and Rab7A mRNA expression, leading to a delay in the endosomal vesicle maturation process. Collectively, our results provide additional insight for increasing PS-ASO efficacy by enhancing endosomal escape, which can further be utilized for other nucleic acid-based modalities. |
| Document Type: |
article |
| File Description: |
electronic resource |
| Language: |
English |
| ISSN: |
2162-2531 |
| Relation: |
http://www.sciencedirect.com/science/article/pii/S2162253123001920; https://doaj.org/toc/2162-2531 |
| DOI: |
10.1016/j.omtn.2023.07.019 |
| Access URL: |
https://doaj.org/article/34962db0b3d4445bb1ec996f342af8fe |
| Accession Number: |
edsdoj.34962db0b3d4445bb1ec996f342af8fe |
| Database: |
Directory of Open Access Journals |
