mRNA as a novel therapeutic class for tissue repair and regenerative medicine

A novel class of therapeutic compounds is currently on a path that could revolutionize large areas of human medicine. Messenger ribonucleic acids – mRNA – are large polynucleotides that, when delivered intracellularly, are translated into proteins by the cell’s own machinery. This means that proteins that are lacking or dysfunctional, thus causing disease, can be produced by the body itself, with all the correct modifications, e.g. glycosylations. mRNA has no or very little inherent toxicity, thus avoiding the side effects mostly seen with small molecule drugs. Areas, where mRNA is set to change therapy, includes vaccines, cancer, a range of metabolic disorders – and, notably, regenerative medicine.

For tissue engineering and regenerative medicine purposes, key applications include (1,2) pluripotent stem cell reprogramming/derivation from somatic cells; stem cell differentiation; cytoprotection and directed angiogenesis; and delivery of Cas endonuclease-encoding mRNA for permanent gene editing. Specifically, for cartilage repair, the main objective in RESTORE, Lin et al. (3) very recently demonstrated in vivo treatment of intervertebral disc disease by nanomicellar delivery of a cartilage-anabolic transcription factor-encoding mRNA. Similarly, Tendulkar et al. (4)delivered synthetic mRNA encoding the Link N peptide and observed increased extracellular matrix synthesis in primary human chondrocytes and mesenchymal stromal cells seeded on titanium scaffolds. They concluded that this method could provide a potent strategy for articular cartilage and intervertebral disc regeneration.

Below is a graph showing the relative number of hits in ISI Web of Science for the three search terms “vaccine”, “mRNA” and the compilation “therapeutic mRNA” OR “mRNA therapy” OR “mRNA drug” OR “mRNA vaccine” for the years 1995 to 2019. The numbers for each search term are scaled against the. year 2019 for that same term; clearly, the generic terms “vaccine” and “mRNA” are much higher in absolute numbers (approx. 250-fold and 400-fold, respectively) than the latter composite term. Yet, the recent publication trend for the therapeutic mRNA field seems exponentially increasing, highlighting the medical potential.

For all RNA drugs, but mRNA in particular, delivery to its intracellular site of action has been one of the biggest hurdles – although one major advantage of RNA therapeutics over the DNA-based cousins is the fact that RNA can be translated in the cytosol, whereas DNA needs to pass even one more cellular barrier – the nuclear membrane – to reach its destination. Nevertheless, the very large, highly polyanionic and rather fragile mRNA strands exhibit virtually no cellular uptake in their native form. The most practically applicable solution seems to be their encapsulation in biocompatible nanoparticles, notably lipid nanoparticles (LNPs) based on synthetic ionizable lipids. A highly promising aspect of this encapsulation strategy is the platformability, i.e. the possibility to decouple the payload biological effect (RNA sequence) from almost all pharmacokinetic and biodistribution properties, which are largely determined by the lipid nanocarrier. This should dramatically facilitate the clinical translation of follow-on medicines. For regenerative medicine and tissue engineering purposes, an additional challenge arises from the need for sustained yet spatially very defined delivery. The proposed strategy to address this requirement frequently involves further encapsulation into macrohydrogels that serve as stationary depots.

Taken together, mRNA as therapeutics seems to have a great potential that is currently on the verge of being realized.

1.  Kwon, H., Kim, M., Seo, Y., Moon, Y.S., Lee, H.J., Lee, K. and Lee, H. (2018) Emergence of synthetic mRNA: In vitro synthesis of mRNA and its applications in regenerative medicine. Biomaterials, 156, 172-193.

2.  Patel, S., Athirasala, A., Menezes, P.P., Ashwanikumar, N., Zou, T., Sahay, G. and Bertassoni, L.E. (2019) Messenger RNA Delivery for Tissue Engineering and Regenerative Medicine Applications. Tissue Eng Part A, 25, 91-112.

3.  Lin, C.Y., Crowley, S.T., Uchida, S., Komaki, Y., Kataoka, K. and Itaka, K. (2019) Treatment of Intervertebral Disk Disease by the Administration of mRNA Encoding a Cartilage-Anabolic Transcription Factor. Mol Ther Nucleic Acids, 16, 162-171.

4.  Tendulkar, G., Ehnert, S., Sreekumar, V., Chen, T., Kaps, H.P., Golombek, S., Wendel, H.P., Nussler, A.K. and Avci-Adali, M. (2019) Exogenous Delivery of Link N mRNA into Chondrocytes and MSCs-The Potential Role in Increasing Anabolic Response. Int J Mol Sci, 20.