On Thursday, 5/28/2020, I attended an ACS webinar about how mRNA technology is being applied in therapeutics and vaccine development. The presentation was given by Dr. James D. Thompson from Moderna, the company that is currently developing one of the most promising vaccines for COVID-19.
I am going to use the most non-technological language to give a summary digest of what he had presented.
The message RNA (mRNA) is the “message” that the body uses to code for proteins. This process happens inside our cells. The proteins that are produced can then be either secreted into intercellular space or in the blood circulation or be incorporated into the cellular membrane.
The technology behind the use of mRNA is to utilize the patient’s own body to produce therapeutic proteins and enzymes.
There are several technical challenges to overcome for mRNA delivery to the patient’s cell.
1) Our body sees any kind of nucleic acids that are being outside of a cell as a threat, for example, a virus genetic material. So the mRNA for coding therapeutic proteins must be well packaged or encapsulated to prevent degradation.
To overcome this challenge, Moderna utilizes a lipid nanoparticle (LNP) formulation as a nano-capsule to protect the mRNA. The LNP is also formulated with components such as cholesterol and ionizable amino lipid, and PEG to enhances its stability, increases control of body distribution and half-life.
The mRNA is also modified to contain building blocks (nucleotides) that are resistant to nuclease degradation, and recognition by immune cell receptors, such as the toll-like receptor.
2) Cells in our body have varying abilities to produce proteins and enzymes. For example, one of our immune cells, B-cells are specialized in producing antibodies. The mRNA in the LNP formulation must be delivered to a part of the body where proteins can be made in abundance.
To overcome this challenge, Moderna chooses to deliver the mRNA liver and spleen. The antibody or other therapeutic proteins are then made by these organs, so-called ectopically produced. The company has confirmed the liver can make functional antibodies.
Moderna stated the mRNA technology, on the other hand, has several advantages over other protein and gene therapy.
1) The technology is a cell-free product. That production of mRNA can be achieved with chemical reactions, that therefore, can limit the batch-to-batch variations.
2) Although the mRNA technology is regulated as gene therapy by the legal standard. The mRNA does not interact with the recipient’s genome and nucleus. The effect of the mRNA is temporary (transient), and dose-dependent
3) In terms of using mRNA technology, the company has successfully demonstrated the production of neutralizing antibodies where it can inhibit the virus entry to host (patient) cells.
4) The mRNA is non-immunogenic for the adaptive immune response
5) Using mRNA for a vaccine is similar to a natural infection, where the viral derived protein is made within a cell. On the same note, then the same principle is also true for generating intracellular therapeutic proteins.
6) In terms of immunology, a protein-based vaccine will need to go through the MHC II processing to present a small peptide for the adaptive immune cells to gain recognition. When a specific mRNA that can code for a viral protein is delivered, the recipient’s body will make the viral protein internally and go through the MHC class I antigen presentation system. This also mimics the natural infection process.
Moderna also stated that mRNAs that encode antibodies with neutralizing ability could have potential as a preventative treatment agent for high-risk personals, such as health care workers, and as an immediate treatment for recent virus exposure and active infection.
Overall, Dr. Thomson presented data that show the proof-of-concept of mRNA-based vaccines and therapies for infectious diseases.
At the end of the presentation, Dr. Thompson stated the mRNA technology in disease treatment is similar to producing an “agonist” that has a positive activity on the targets, where other nucleic acids based therapy act more like an antagonist (blocker effects).
In my personal perspective, I am in agreement with the final statement from Dr. Thompson. My research in aptamer has always aimed for the generation of blockers, where they are intended to stop a process from happening.
In conclusion, I believe Moderna’s mRNA technology is quite promising in most of their earlier trials. My only reservation in their technology without further examing their published data and research paper is within its LNP formulation. Polyethylene glycol or PEG has been shown to elicit the generation of anti-PEG antibodies in recipients’ bodies. The PEG used in the LNP function has a potential of the same risk. I would be interested to see how the company overcome this barrier in their Phase III clinical trial of their COVID-19 vaccine (mRNA -1273) study.
Written by Dr. Ka Lok Hong, May 30th 2020
