MicroRNAs Enable mRNA Therapeutics to Selectively Program Cancer Cells to Self-Destruct
Open accessAbstract
The advent of therapeutic mRNAs significantly increases the possibilities of protein-based biologics beyond those that can be synthesized by recombinant technologies (eg, monoclonal antibodies, extracellular enzymes, and cytokines). In addition to their application in the areas of vaccine development, immune-oncology, and protein replacement therapies, one exciting possibility is to use therapeutic mRNAs to program undesired, diseased cells to synthesize a toxic intracellular protein, causing cells to self-destruct. For this approach to work, however, methods are needed to limit toxic protein expression to the intended cell type. Here, we show that inclusion of microRNA target sites in therapeutic mRNAs encoding apoptotic proteins, Caspase or PUMA, can prevent their expression in healthy hepatocytes while triggering apoptosis in hepatocellular carcinoma cells.
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Regulation of other tumour-associated genes, such as PLK1, Bax, Maspin, PUMA and PTEN, can delay tumour growth in vivo.
“Similarly, the regulation of other tumour-associated genes, such as PLK1 (ref.133), Bax219, Maspin37, PUMA70 and PTEN220, can delay tumour growth in vivo.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [70]
The risk of off-target gene editing of bystander cells can be mitigated by the addition of tissue- or cell-specific miR binding sites to the mRNA sequence, which results in tissue-specific suppression of mRNA translation.
“This risk can be mitigated by the addition of tissue- or cell-specific miR binding sites to the mRNA sequence, which results in tissue-specific suppression of mRNA translation (47, 48).”
From CRISPR-Cas9 genome editing using targeted lipid nanoparticles for cancer therapy (2020) · cites this paper as [47]
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- Authors
- Jain, R., Frederick, J. P., Huang, E. Y., Burke, K. E., Mauger, D. M., Andrianova, E. A., Farlow, S. J., Siddiqui, S., Pimentel, J., Cheung-Ong, K., McKinney, K. M., Köhrer, C., Moore, M. J., & Chakraborty, T.
- Affiliations
- Moderna Therapeutics (United States) (US)
- Corresponding author
- Jain, Ruchi
- Venue
- Nucleic Acid Therapeutics
- Publisher
- SAGE Publications
- Published
- 2018-10
- Volume
- 28
- Issue
- 5
- Pages
- 285-296
- ISSN
- 2159-3337 (ISSN-L)
- 2159-3345
- PMC
- PMC6157376
- OpenAlex
- W2885809926
- Cited by
- 164
- References
- 36
- Citations by year
- 2026: 20 · 2025: 29 · 2024: 26 · 2023: 23 · 2022: 30 · 2021: 18 · 2020: 9 · 2019: 7 · 2018: 1 · 2014: 1
- FWCI
- 3.11
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Nucleic Acid Therapeutics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Moderna
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Keywords
- microRNA binding sites, mRNA therapeutics, apoptosis, caspases, PUMA, hepatocellular carcinoma, hepatocytes, selective toxicity
- MeSH terms
- RAW 264.7 Cells, Animals, HeLa Cells, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Proto-Oncogene Proteins, RNA, Messenger, Gene Expression Regulation, Neoplastic, Apoptosis, Caspases, Hepatocytes, MicroRNAs, Apoptosis Regulatory Proteins, Mice, Primary Cell Culture
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