A first-in-class fully modified version of miR-34a with outstanding stability, activity, and anti-tumor efficacy
Abstract
Altered by defects in p53, epigenetic silencing, and genomic loss, the microRNA miR-34a represents one of the most clinically relevant tumor-suppressive microRNAs. Without question, a striking number of patients with cancer would benefit from miR-34a replacement, if poor miR-34a stability, non-specific delivery, and delivery-associated toxicity could be overcome. Here, we highlight a fully modified version of miR-34a (FM-miR-34a) that overcomes these hurdles when conjugated to a synthetically simplistic ligand. FM-miR-34a is orders of magnitude more stable than a partially modified version, without compromising its activity, leading to stronger repression of a greater number of miR-34a targets. FM-miR-34a potently inhibited proliferation and invasion, and induced sustained downregulation of endogenous target genes for >120 h following in vivo delivery. In vivo targeting was achieved through conjugating FM-miR-34a to folate (FM-FolamiR-34a), which inhibited tumor growth leading to complete cures in some mice. These results have the ability to revitalize miR-34a as an anti-cancer agent, providing a strong rationale for clinical testing.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Sep 05, 2023
- Source ID
- 10.1038/s41388-023-02801-8
Entities
People
- Ahmed Mansour
- Andrea Kasinski
- Harish Kothandaraman
- Ikjot S Sohal
- Kasireddy Sudarshan
- Nadia M Atallah
- Philip S. Low
- Shreyas G Iyer
Organizations
- National Cancer Institute
- United States Department of Defense
- United States Department of Health and Human Services