Don’t kill the messenger: The potential of mRNA therapies
Messenger ribonucleic acid (mRNA)- based therapies represent a new era in modern medicine. Synthetic mRNA can encode and express any protein without entering the nucleus and, consequently, the risk of genomic integration or mutagenesis. The fast, effective, and temporary nature of mRNA-encoded proteins makes them attractive tools to address several conditions, from infectious diseases to cancer and genetic disorders.
Once viewed as a mere transient intermediary in the central dogma of molecular biology, mRNA has evolved into a revolutionary therapeutic platform. The rapid development of COVID-19 vaccines, along with the increasing investigation of cancer treatments and gene editing, illustrates that mRNA-based therapies are changing the rules of medicine. These advancements pose an exciting glimpse into a future where diseases can be tackled at their origin.
The discovery of mRNA dates back to the early 1960s, implying decades of foundational research that led to its therapeutic application1. Nonetheless, the inherent instability and immunogenicity of naked mRNA molecules presented complex barriers. It wasn't until the late 1980s and early 1990s that researchers began to explore the possibility of using mRNA as a drug, with pioneering work focusing on in vitro transcription and lipid-based delivery systems2,3. Yet, progress remained slow, obstructed by technical challenges and widespread disbelief about the practicality of mRNA-based treatments.
The decisive moment arrived with the development of lipid nanoparticle (LNP) technology and modifications to mRNA sequences that reduced immune activation and enhanced stability4,5. These breakthroughs, together with the urgent need for a quick response to the COVID-19 pandemic, pushed mRNA vaccines into the global spotlight, emphasizing their remarkable potential and confirming years of dedicated research6.
Mechanism of action
mRNA basics
Messenger RNA is the most diverse category of RNA, with many different molecules present in a cell at any given time. mRNA transmits genetic information, known as transcripts, from DNA to ribosomes, where proteins are synthesized. Essentially, it operates as a template for protein production. Every mRNA molecule corresponds to a specific protein, and the sequence of nucleotides in the mRNA dictates the protein's amino acid sequence7.
Therapeutic mechanism
mRNA-based drugs work by delivering synthetic mRNA into the body. After entering the cells, ribosomes translate the mRNA to create a particular protein8. This protein can then perform its designed function, for instance, triggering an immune response, repairing damaged tissues, or replacing a missing or faulty protein. This precise approach allows for the rapid and cost-effective production of various proteins, making mRNA-based therapies exceptionally versatile.
Applications of mRNA-based therapies
Vaccines
One of the most notorious applications of mRNA technology is in developing vaccines. mRNA vaccines act by encoding a piece of the virus's spike protein, which is harmless on its own9. When mRNA is introduced into the body, cells generate the spike protein, which is vital for recognizing receptors and facilitating the fusion of cell membranes. This alerts the immune system to identify the protein as foreign and triggers an immune response. As a result, the immune system becomes prepared to combat the actual virus if encountered in the future. The COVID-19 vaccines developed by pharmaceutical companies in 2020 are prime examples of this technology in action.
Cancer treatments
mRNA-based technologies are also being explored for cancer treatment10. These treatments are designed to synthesize proteins that stimulate the immune system to attack cancer cells. For example, mRNA vaccines can encode tumor-specific antigens, guiding the immune system to recognize and destroy cancer cells. In addition, mRNA can be employed in CAR-T cell therapy, where T cells are engineered to target cancer cells more efficiently11.
Other applications
Besides vaccines and cancer treatments, mRNA-based therapies have potential applications in treating genetic disorders and infectious diseases12. For genetic disorders, mRNA can be used to replace or supplement missing or defective proteins or genes for conditions like cystic fibrosis, hemophilia, and muscular dystrophy. In infectious diseases such as influenza, Zika, and rabies, mRNA can be applied to produce proteins that neutralize pathogens or enhance the immune response.
Development and delivery
mRNA modifications
Several modifications are made to the mRNA molecules to enhance the stability and efficacy of mRNA-based therapies. These include changes to the nucleotide sequence to prevent cellular enzyme degradation and adding a 5' cap and a poly(A) tail to improve translation efficiency and stability13. Moreover, untranslated regions (UTRs), which are found at both the 5' and 3' ends of mRNA, do not code for proteins but also play crucial roles in stability, translation efficiency, and overall effectiveness.
Delivery systems
The effective delivery of mRNA into cells is imperative for the success of mRNA-based drugs. As previously mentioned, LNPs are the most commonly used delivery system. LNPs protect the mRNA from degradation and facilitate its entry into cells5. Alternative delivery methods are also being developed, including polymer-based nanoparticles, such as synthetic and natural cationic polymers, as well as viral vectors like adenoviral and lentiviral transmitters14. The choice of delivery system depends on the specific application and the target cells involved.
Challenges and future directions
Technical challenges
Although mRNA-based drugs have promising possibilities, numerous technical problems persist. These challenges include ensuring the stability of mRNA molecules, preventing unintended immune responses, and achieving efficient delivery to target cells. Overcoming these obstacles is critical for the extensive implementation of mRNA medicines15.
Prospects
The prospects of mRNA-based therapies are encouraging, as active research seeks to overcome current limitations and broaden the range of applications. Innovations in mRNA modifications, delivery systems, and manufacturing processes are anticipated to enhance the efficacy and availability of these treatments on a global scale.
mRNA therapeutics hold a strategic progression in biomedical sciences. They propose a versatile and efficient method of treating multiple diseases. From vaccines to cancer treatments, the potential applications of mRNA technology are vast and promising.
As we look to the future, mRNA-based therapies promise to transform medicine by delivering rapid, targeted, and effective treatments for various conditions. Ongoing research and development is essential to address current challenges and fully realize the potential of this advanced technology.
References
1. Jacob F. and Monod J., "Genetic Regulatory Mechanisms in the Synthesis of Proteins," J. Mol. Biol. 3, 318-356 (1961).
2. Malone, R W et al. “Cationic liposome-mediated RNA transfection.” Proceedings of the National Academy of Sciences of the United States of America vol. 86, 6077-81 (1989).
3. Şahin, U.; Kariko, K.; Türeci, Ö. mRNA-based therapeutics—Developing a new class of drugs. Nat. Rev. Drug Discov. 13, 759–780 (2014).
4. Pardi, N., Hogan, M. J., Porter, F. W. & Weissman, D. mRNA vaccines — a new era in vaccinology. Nat. Rev. Drug Discov. 17, 261–279 (2018).
5. Hou, X., Zaks, T., Langer, R. et al. Lipid nanoparticles for mRNA delivery. Nat Rev Mater 6, 1078–1094 (2021).
6. Chavda, Vivek P et al. “mRNA-Based Vaccines and Therapeutics for COVID-19 and Future Pandemics.” Vaccines vol. 10,12 2150 (2022).
7. Alberts B, Johnson A, Lewis J, et al. New York: Garland Science; (2002).
8. Qin, Shugang et al. “mRNA-based therapeutics: powerful and versatile tools to combat diseases.” Signal transduction and targeted therapy 7,1 166. (2022).
9. Demongeot, Jacques, and Cécile Fougère. “mRNA COVID-19 Vaccines-Facts and Hypotheses on Fragmentation and Encapsulation.” Vaccines 11,1 40 (2022).
10. Sun, Han et al. “mRNA-Based Therapeutics in Cancer Treatment.” Pharmaceutics 15,2 622 (2023).
11. Rurik, Joel G et al. “CAR T cells produced in vivo to treat cardiac injury.” Science (New York, N.Y.) 375, 91-96 (2022).
12. Al Fayez, Nojoud et al. “Recent Advancement in mRNA Vaccine Development and Applications.” Pharmaceutics 15,7 (2023).
13. Kim, Sun Chang et al. “Modifications of mRNA vaccine structural elements for improving mRNA stability and translation efficiency.” Molecular & cellular toxicology 18,1-8 (2022).
14. Chen, Qiang et al. “Unleashing the potential of mRNA: Overcoming delivery challenges with nanoparticles.” Bioengineering & translational medicine 10,2 (2024).
15. Eftekhari, Zohre et al. “Advancements and challenges in mRNA and ribonucleoprotein-based therapies: From delivery systems to clinical applications.” Molecular therapy. Nucleic acids 35, 3 (2024).