Targeted Delivery of Antisense Oligonucleotides Through Angiotensin Type 1 Receptor.
Carol KuoMehran NikanSteve T YehAlfred E ChappellMichael TanowitzPunit P SethThazha P PrakashAdam E MullickPublished in: Nucleic acid therapeutics (2022)
We evaluated the potential of AGTR1, the principal receptor for angiotensin II (Ang II) and a member of the G protein-coupled receptor family, for targeted delivery of antisense oligonucleotides (ASOs) in cells and tissues with abundant AGTR1 expression. Ang II peptide ASO conjugates maintained robust AGTR1 signaling and receptor internalization when ASO was placed at the N-terminus of the peptide, but not at C-terminus. Conjugation of Ang II peptide improved ASO potency up to 12- to 17-fold in AGTR1-expressing cells. Additionally, evaluation of Ang II conjugates in cells lacking AGTR1 revealed no enhancement of ASO potency. Ang II peptide conjugation improves potency of ASO in mouse heart, adrenal, and adipose tissues. The data presented in this report add to a growing list of approaches for improving ASO potency in extrahepatic tissues.
Keyphrases
- angiotensin ii
- angiotensin converting enzyme
- induced apoptosis
- vascular smooth muscle cells
- cell cycle arrest
- gene expression
- heart failure
- binding protein
- endoplasmic reticulum stress
- poor prognosis
- insulin resistance
- machine learning
- type diabetes
- metabolic syndrome
- cell proliferation
- single cell
- big data
- pi k akt