Faculty, Staff and Student Publications

Publication Date

2-2-2024

Journal

Neuro-Oncology

Abstract

Background: Glioblastoma (GBM) has poor prognosis due to ineffective agents and poor delivery methods. MicroRNAs (miRs) have been explored as novel therapeutics for GBM, but the optimal miRs and the ideal delivery strategy remain unresolved. In this study, we sought to identify the most effective pan-subtype anti-GBM miRs and to develop an improved delivery system for these miRs.

Methods: We conducted an unbiased screen of over 600 miRs against 7 glioma stem cell (GSC) lines representing all GBM subtypes to identify a set of pan-subtype-specific anti-GBM miRs and then used available TCGA GBM patient outcomes and miR expression data to hone in on miRs that were most likely to be clinically effective. To enhance delivery and expression of the miRs, we generated a polycistronic plasmid encoding 3 miRs (pPolymiR) and used HEK293T cells as biofactories to package pPolymiR into engineered exosomes (eExos) that incorporate viral proteins (Gag/VSVg) in their structure (eExos+pPolymiR) to enhance function.

Results: Our stepwise screen identified miR-124-2, miR-135a-2, and let-7i as the most effective miRs across all GBM subtypes with clinical relevance. Delivery of eExos+pPolymiR resulted in high expression of all 3 miRs in GSCs, and significantly decreased GSC proliferation in vitro. eExos+pPolymiR prolonged survival of GSC-bearing mice in vivo when compared with eExos carrying each of the miRs individually or as a cocktail.

Conclusion: eExos+pPolymiR, which includes a pan-subtype anti-glioma-specific miR combination encoded in a polycistronic plasmid and a novel exosome delivery platform, represents a new and potentially powerful anti-GBM therapeutic.

Keywords

Humans, Animals, Mice, MicroRNAs, Glioblastoma, Exosomes, HEK293 Cells, Brain Neoplasms, Cell Line, Tumor, Glioma, Gene Expression Regulation, Neoplastic, exosomes, glioblastoma, microRNA

DOI

10.1093/neuonc/noad199

PMID

37847405

PMCID

PMC10836765

PubMedCentral® Posted Date

10-17-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Share

COinS
 
 

To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.