The ability of microRNAs (miRNAs) to regulate gene expression in diverse biological processes provides new and potentially powerful candidates for therapeutic intervention. But, to date, no miRNAs have been approved for clinical treatment.
What’s blocking the road from bench to bedside?
Their transition into the clinic has been delayed by reduced stability, potential immunogenic effects, and a need for safer delivery vehicles.
To overcome these limitations, Abdelaal et al. propose a series of modifications on the miRNA-34a, published last month on Oncogene, allowing a growth arrest in breast cancer tumors for 21 days, induced in female mice.
A stable, active, and anti-tumoral version of miR-34a
miRNA-34a is a well-known microRNA able to downregulate several oncogenic pathways involved in cell proliferation, migration and invasion, resistance to apoptosis, and immune evasion, which makes it a perfect candidate as a therapeutic molecule to fight cancer.
Abdelaal et al. have designed a fully modified miR-34a to overcome the characteristic miRNA limitations, consisting of an asymmetric pattern that contains a guide strand annealed to a complementary strand. Each strand includes an alternating pattern of 2′-O-methyl and 2′-fluoromodified sugars and phosphorothioate linkages at the 3′ and 5′ ends to reduce immunogenicity and provide exonuclease resistance, as shown in Figure 1.
Figure 1. Fully modified miR-34a to increase stability, reduce immunogenicity, and ensure targeted delivery to cancer cells. Adapted from Abdelaal, A.M., Sohal, I.S., Iyer, S. et al. A first-in-class fully modified version of miR-34a with outstanding stability, activity, and anti-tumor efficacy. Oncogene (2023).
The team added a vitamin folate molecule as a targeting ligand to ensure targeted delivery. The folate receptor is overexpressed in breast, lung, ovarian, colorectal, and other cancers.
What’s the impact of these modifications on miRNA activity?
The modification pattern extends miR-34a stability compared to unmodified or partially modified miRNA. It also enhances the ability of miR-34a to downregulate its known/predicted targets, such as MET, CD44, and AR genes.
The modifications provide stability against nucleases and enhance silencing activity, culminating in reduced therapeutic dosing of only 1.5 nmol in tumor-bearing mice.
The inhibitory effect of the modified miRNA on tumor growth in vivo was robust, resulting in a tumor-static apparent impact, and it also reduced the initial volume of tumors in two mice by 45-75 % by the end of the 21-day dosing period, with one complete cure. Regarding the immune response, the miRNA did not cause a significant increase in cytokine levels above the negative control.
Lipid nanoemulsions as modified miRNA delivery vehicles
To completely exploit the potential of these modified miRNAs, they can be combined with lipid-based delivery vehicles; in fact, the authors conclude the paper with this idea:
“Thus, one could imagine encapsulating FM-miR-34a in larger lipid nanoparticles, which could increase circulation half-life while still affording protection intracellularly.”
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