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mRNA may be a modality whose chief advances are yet to come.
The term microbiome may have first been used in an agriculture paper (1), but widespread traction was sparse until Francis Collins (then head of the National Human Genome Research Institute) talking through upcoming funding limits for simply sequencing yet another organism, with Broad Institute head, Eric Lander, had a true eureka moment, to seize upon sequencing the human microbiome—skin, gut, hair, and so forth, for multiple funding projects going forward. Suddenly all things microbiome became in vogue. However, as recently as February 2020, scientific papers were still proposing vague notions that, “The mechanisms by which microbiomes impact on cancers can yield new diagnostics and treatments, but much remains unknown” (2). What had seemed administrative legerdemain at that time of Collins eureka moment is, in 2023, absolutely a therapeutic window to drill down on. The tumor microenvironment as therapeutic approach has come of age, and the tool of the hour is messenger RNA (mRNA).
Acknowledging that bacteria and fungi form complex colonies with solid tumors, an approach to unravel this microbiome community was developed with mRNA molecules encoded to produce a toxin lethal to cohabitating bacteria. In this experiment, pseudomonas exotoxin A domain III was packaged into lipid nanoparticles and injected into the tumor bed. “We hypothesized that encoding the active domain only, without the binding and translocation domains of the original toxin, will allow potent intracellular effect upon mRNA translation, while reducing the risk of side-off effects in case of toxin release from target cells,” related professor Dan Peer, co-lead author of the study (3). Unlike chemotherapy where resistance gathers pace during extended exposure, this approach is easily amenable to simply switching to a different natural toxin. The study goes on to describe that most of the lipid nanoparticles reached cancer cells, destroying 44–60% of them.
While the history of drug discovery science is replete with false dawns, it is encouraging to see mRNA make an alliance with deeper understanding of the mechanics of the tumor microbiome. mRNA may be a modality whose chief advances are yet to come.
1. Whipp, et al., Fungi in Biological Control Systems. Manchester University Press. 1988.
2. Xavier, J.; Young, V.; Skufca, J., et al. The Cancer Microbiome: Distinguishing Direct and Indirect Effects Requires a Systemic View. Trends in Cancer. 2020 March 6(3), doi: 10.1016/j.trecan.2020.01.004.
3. Granot-Matok, Y.; Ezra, A.; Peer, D.; et al. Lipid Nanoparticles-loaded with Toxin mRNA Represents a New Strategy for the Treatment of Solid Tumors. Thernostics. 2023 July.
Chris Spivey is editorial director for Pharmaceutical Technology.
Vol. 47, No. 8
When referring to this article, please cite it as Spivey, C. New Magic from mRNA. Pharmaceutical Technology 2023 47 (8).