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Although messenger ribonucleic acid (mRNA) is used by all organisms to make proteins, it is rarely used in drug research and development. With many are enthusiastic about the new COVID-19 vaccines, the development of a series of mRNA drugs represented by mRNA vaccines has excited the researchers even more. However, the road to mRNA drugs development is not smooth. What is the current status and prospects of their applications?
What Are mRNA Drugs?
Traditional drugs function mostly by acting on protein molecules, produce therapeutic effects. Therefore, the development of traditional drugs not only relies on the exploration of molecular substances that can modify proteins, but also depends on a deep and specific understanding of the mechanism of disease, to achieve good efficacy and safety.
mRNA guides protein synthesis directly. To complete tasks such as destroying invading bacteria or viruses, eliminating cancer cells, correcting abnormal protein expression, etc., direct protein guidance through mRNA simplifies the problems posted by traditional drug development, which is the idea behind mRNA drug design.
Advantages Of mRNA Drugs
- mRNA drugs can regulate gene expression without entering the nucleus or changing the human genome, and use the cell’s own mechanism to naturally produce fully functional proteins, thereby treating incurable diseases.
- mRNA drugs have some characteristics similar to traditional drugs, such as the ability to repeat or adjust the dose of drugs under long-term conditions.
- The process of mRNA drug development, from the selection of target genes to the development of candidate products, can be vary faster.
- mRNA drug design can be applied to the development of a variety of drugs for cancers, and infectious diseases.
Evaluation Standard Of mRNA Drugs
Qualified mRNA drugs should be effective and with controllable, safety and stability.
- Effectiveness
Taking mRNA vaccines as an example, the effectiveness of mRNA drugs is mainly determined by the following aspects:
- Delivery efficiency
- Translation efficiency
- Immunogenicity
Since mRNA is easily degraded by RNase, mRNA drugs need to be efficiently targeted to specific organs.
The rate of mRNA translation into proteins or polypeptides should be efficient.
Effective design for disease pathways.
- Safety
- If the production process may involve new immunomodulatory components and excipients, the safety of these added substances needs to be verified.
- The immunogenicity of mRNA can sometimes cause unnecessary immune-related side effects.
- Stability
Because mRNA is very unstable, the stability of the mRNA drugs during preparation can have a huge impact on their accessibility.
mRNA Drugs Face Many Challenges.
- First and foremost, mRNA needs to be specifically delivered to target tissues or target cells while avoiding the immune system.
- If the body’s immune system is triggered during the delivery of mRNA drugs, the body’s immune response may quickly eliminate these foreign substances, thereby limiting the production of target proteins and weakening the therapeutic effects of mRNA drugs.
- In addition, we also need to "cheat" the ribosome to think that the delivered mRNA is naturally produced, so that they can accurately read the instructions and produce the correct target protein.
The modification of mRNA has solved this problem to a certain extent, but more studies are still needed to manage these scientific and technical challenges.
Figure 2: Modification of the mRNA sequence makes it more effective.
Delivery System Of mRNA Drugs
The focus of the mRNA drug delivery system is to reduce the degradation and, improve protein expression rate, immunogenicity, and other indicators. Existing non-viral delivery systems include LNP, LPX (cationic liposomes), LPP (polymer nanocarrier liposomes), etc.
- LNP (lipid nanoparticles) is currently the mainstream delivery system for mRNA drugs.
- Due to the potential application limitations of LNP technology, the industry is also exploring other lipid complexes and polymers as delivery vehicles.
When using the LNP system, consider: 1) the proportion of ingredients and the type of phospholipid; 2) biodegradation (involving safety and efficiency); 3) lipid saturation; 4) targeting of the delivery system.
Figure 1: The mRNA encapsulated by lipid nanoparticles is transported to the target cell, recognized, and translated by the target cell’s ribosomes and other organelles, and finally restores, enhances, weakens, or confers new protein functions to achieve the goal of treating or preventing diseases.
Where Does the Development Of mRNA Drugs Stand?
- As a new drug platform, mRNA has a wide range of applications: treating tumors (personalized antigens or tumor immunity) and, infectious diseases, protein replacement therapy, etc.; express antigens, antibodies, etc.
- Judging from the number of clinical trials for various indications, tumors accounted for the most, nearly 75%; the second is infectious diseases. The outbreak of COVID-19 has prompted a rapid increase in the number of related clinical trials; And finally, protein replacement therapy comes at last when explored as an mRNA application.
- mRNA technology is still at the exploratory stage.
- The research and development of mRNA drugs have mainly stayed in clinical phase 1 and phase 2 in the past, but the progress was greatly accelerated, due to the urgent need for the COVID-19 vaccine. Currently, Pfizer/BioNtech and Moderna's COVID-19 vaccines have received emergency approvals from many countries. In terms of tumors, mRNA drugs are still test in preclinical or early clinical stages.
Although the research and development of mRNA drugs are more efficient than traditional drugs in terms of structural design, both inevitably need an extremely time-consuming human trial phase before they are put into use. But in general, research on mRNA drugs has gradually matured. The many advantages of mRNA therapy will inevitably lead to the development of more mRNA drugs in the future.
* Only for research. Not suitable for any diagnostic or therapeutic use.
