mRNA: the therapeutics of the future! (or, 2021 the way research is going…)

Today’s top selling drugs are mostly biologics, which means proteins (e.g., monoclonal antibodies) being used as medicine. The global therapeutic monoclonal antibody market was valued at approximately US$115.2 billion in 2018, and is expected to generate revenue of $150 billion by the end of 2019, and $300 billion by 20251. Thus, the market for therapeutic antibody drugs has experienced an explosive growth with new drugs being approved for treating various human diseases, including many cancers, autoimmune, metabolic and infectious diseases, which have increasingly fewer adverse effects due to their high specificity. 

But, these types of treatments carry their own limitations. Besides of a long period of development, they can only access the extracellular space, the serum. Yet, ~2/3 of the human proteome are intracellular or transmembrane proteins; which means that biologics cannot treat disorders that are caused by these types of proteins. 

As such, an alternative mechanism to make these proteins is needed in order to go further in the advancement of therapeutics. 

One such mechanism, is to supply the mRNA that encodes that protein. As such, any protein can become a drug. And, since only the coding region varies from mRNA-drug to mRNA-drug; once the delivery vehicle problem is resolved (e.g., using lipid nanoparticles), the development of new mRNA drugs should be quite fast in comparison with other types of medicine.

The other positive aspect of mRNA as therapeutics, is that it can be used in many different types of modalities: prophylactic vaccines, cancer vaccines, intertumoral immune-oncologicals, localized regenerative therapeutics, systemic secreted medicine, and cell surface therapeutics…

Another positive aspect of mRNA-drugs is that several mRNAs can be delivered at once, like in the case of prophylactic vaccines (e.g., Moderna Therapeutics Cytomegalovirus (CMV) mRNA vaccine delivers 6 different mRNAs to encode a multiprotein complex). 

Or, another possibility, is the personalization of cancer vaccines, where different patient-specific neoepitopes are sequenced, and mRNA is created that encodes those 20-35 specific tumour-neoepitopes. 

Those mRNAs can also encode cytokines, that are able to boost the immune system to attack a tumour, like intertumoral immune-oncologicals therapeutics. 

In the field of localized regenerative therapeutics, there is currently a project between Moderna Therapeuticsand AstraZeneca in Phase II clinical trials, where Vascular Endothelial Growth Factor-A (VEGFA) mRNA is injected NAKED, without lipid nanoparticles, directly into the heart muscle of patients with a recent Myocardial Infarction (MI) to help rebuild blood vessels. 

Of course, many challenges still exist. 

mRNA needs to be rightly sequenced and be made at high purity. It also needs to have the ability to avoid the innate immune sensors, like Toll-like receptors (TLR) in the endoplasmic reticulum, and RIG-I/MDA-5-like receptors in the cytoplasm. What researchers do to avoid the first ones (TLRs) is to use a Pseudouridine, which looks like a Uridine and still base-pairs, but escapes TLR recognition. To avoid the RIG-I/MDA-5-like receptors, researchers need to highly purify the therapeutic mRNA, so that no double-stranded RNA exists (or, reengineer T7 RNA polymerase not to produce dsRNA at all).

The next step on making a good mRNA-drug is to find an efficient delivery method. For that, most therapeutics will need some sort of mRNA encapsulation with Lipid nanoparticles, which are akin to endogenous lipid transport complexes, similar to Very-Low Density Lipoproteins (VLDLs).

Finally, in order to make a good mRNA-drug, there needs to be knowledge on how to engineer the best mRNA sequence for a particular purpose. As such, there needs to be translation initiation fidelity, so that it always starts in the right place and there’s faithful decoding; and, also, the ribosome needs to stop in the right place. There needs to be high translation efficiency, a functional mRNA half-life, and hit the correct cell type, by putting off-logic gates, like microRNAs target sites in the 3’prime UTR and causing the mRNA to be degraded in case it hits an undesired cell type. Also, the mRNAs need to be tailored to the protein type (e.g., secreted, mitochondrial).

So, let’s see what the future brings from mRNA therapeutics…

References:

1          Lu, R.-M. et al. Development of therapeutic antibodies for the treatment of diseases. Journal of Biomedical Science 27, 1, doi:10.1186/s12929-019-0592-z (2020).

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