mRNA Therapeutics And Its Future
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Updated: 2 days ago
Recent advances in mRNA molecular medicine has enabled mRNA-based therapeutics to enter into a new technological revolution of medicine. The success of those programs serves as a vital industrial validation for lipid nanoparticle (LNP) delivery systems.
Rapid advancements have enabled the production of many functional complex proteins or peptide sequences in the human body by introducing mRNA as a therapeutic agent or as a vaccine. By delivering specific genetic sequences, we can now order the human body to generate its own targeted responses towards chronic autoimmune disorders or mutations. This represents the shift of medicine from a more “chemical” based into a “information” based cure, where the drug is a set of instructions that allows the body to produce it in a more precise and adaptable manner into the body instead of
molecules that alter the body’s chemistry.
The Anatomy of Synthetic mRNA
To function effectively within the human cell, the mRNA must mimic the transcripts from the targeted eukaryotic cell. The optimization of these five essential regions determines the stability, yield, and translation efficiency of the therapy:
mRNA Regions | Function |
5’Cap |
|
Open Reading Frame (ORF) |
|
3’ and 5’ Untranslated region (UTR) |
|
Poly[5’] Tail |
|
Personalized Immunotherapy
The most transformative application of mRNA is the development of therapeutic cancer vaccines. Unlike traditional vaccines, these are designed to treat an existing disease by training the immune system to recognize tumor markers of interest.
Feature | Tumor-Associated Antigens (TAAs) | Tumor-Specific Antigen (TSAs) |
Description | Antigens overexpressed in tumors but also present in healthy cells | Unique antigens resulting from somatic mutations in cancer cells |
Precision | Lower specificity; prone to host tolerance | High specificity. |
Workflow | Standardized off-the-shelf production is possible | Requires high throughput sequencing and custom manufacturing. |
Personalized vaccines such as BNT122 and mRNA-4157, which are used to target melanoma, are currently in clinical trials, using up to 20 and 34 patient specific neoantigens respectively to trigger T-cell responses in the patients.
Protein replacement.
mRNA offers a promising solution for diseases that were inherited genetically due to a single faulty gene. Instead of supplementing the body with expensive recombinant proteins, mRNA teaches the liver or other organs to synthesize them itself. Companies such as Translate Bio utilized nebulized mRNA, which are delivered via aerosol inhalation on MRT5005 in order to restore mutated CFTR proteins, which disrupts chloride and water transportation what causes a thick, sticky mucus that accumulates in organs such as the lungs and pancreas. Leading to Cystic Fibrosis, causing persistent phlegm and lung infection. Methylmalonic acidaemic, a recessive metabolic disorder caused by deficiency or absence of the enzyme methylmalonyl-CoA epimerase or methylmalonyl-CoA mutase that leads to high methylmalonic acid concentrations, leading to lethargy and hypotonia. Studies on Mus musculus (mice) mRNA delivery has shown a 60-90% reduction in methylmalonic acid in its body. Haemophilia, a genetic bleeding disorder which was caused by mutations in haemophilia A (FVIII) have been suitable targets for mRNA based therapy. A study done by Russick et al., (2019) has successfully corrected the bleeding defect within 4-6after the treatment for 4-6 days utilizing B domain-deleted FVIII-mRNA to FVIII-deficient mice.
Future insights
While the potential of mRNA is vast, expanding its use beyond vaccines requires overcoming several biological and engineering challenges as scientists are working to improve the stability, immunogenicity and delivery mechanisms of these therapies. Delivery is one of the main issues, usually lipid nanoparticles would naturally accumulate in the liver, however, reaching extra hepatic tissues such as the brain and heart remains a problem. Developing next-generation delivery vehicles that can selectively target these organs without causing toxicity to the human body is a primary focus in current research. mRNA naturally degrades over time, which causes its therapeutic effects to be temporary. For chronic conditions that require a lifelong supply of a missing protein, patients would require repeated doses, which can trigger undesirable immune responses due to immunogenicity and reactogenicity, in which the body begins to attack itself out of defense. Currently, the fragility of RNA requires constant extreme cold-chain logistics. Therefore, future innovations are focusing on a more thermostable formulation such as lyophilization (freeze-drying) and novel lipid nanoparticle structures that ensures mRNA drugs can remain stable at room temperatures.
Conclusion
mRNA based therapeutics possess an excellent safety profile as they don't enter the cell’s nucleus and pose no risk of integration. However, they remain fragile, as we refine the duration of expression and delivery efficiency, we could potentially unlock the ability to treat the human body as a programmable biological platform.
References
Hamideh Parhiz, Atochina-Vasserman, E. N., & Weissman, D. (2024). mRNA-based therapeutics: looking beyond COVID-19 vaccines. The Lancet, 403(10432).
Martini, P. G. V., & Guey, L. T. (2019). A New Era for Rare Genetic Diseases: Messenger RNA Therapy. Human Gene Therapy, 30(10), 1180–1189.
Qin, S., Tang, X., Chen, Y., Chen, K., Fan, N., Xiao, W., Zheng, Q., Li, G., Teng, Y., Wu, M., & Song, X. (2022). mRNA-based therapeutics: powerful and versatile tools to combat diseases. Signal Transduction and Targeted Therapy, 7(1), 1–35.
Russick, J., Delignat, S., Milanov, P., Christophe, O., Boros, G., Denis, C. V., Lenting, P. J., Kaveri, S. V., & Lacroix-Desmazes, S. (2019). Correction of bleeding in experimental severe hemophilia A by systemic delivery of factor VIII-encoding mRNA. Haematologica, haematol.2018.210583.
11 Things to Know About mRNA Vaccines for COVID-19 | Benaroya Research Institute. (n.d.). Www.benaroyaresearch.org.
This article was prepared by Chin Yu Xuan (Taylor's University).
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