In his "Letter to the Readers", co-editor-in-chief of the journal ONCOLOGY Howard S. Hochster, MD, reviews the development of mRNA technology, especially as it applies to vaccines against COVID-19.
We have all learned the central dogma of molecular biology: the DNA code is translated to messenger RNA which, in turn, is transcribed to proteins. To date, cancer therapeutics have focused on DNA by causing damage in replication or on proteins by targeting the molecule of interest with signal transduction inhibitors or antibodies. The excellent review in this article by ONCOLOGY® editorial board member Mehmet Sitki Copur, MD, FACP, explains the basis for progress in the area of exploiting the middle step using mRNA and reviews a number of new trials using this technology.
The use of artificial mRNAs provides a real opportunity to make any protein of interest, or even multiple proteins, which may induce therapeutic immune reaction. The story of mRNA from underappreciated lab curiosity to therapeutic entity is one of skepticism, appreciation of its potential, extensive investment by public and private entities, and entrepreneurism leading to the current vaccines for SARS-CoV2 from Moderna and Pfizer-BioNTech. I refer readers to an excellent article from STAT by Damian Garde and Jonathan Saltzman.1 The field of mRNA therapeutics, despite validation in murine models, was treated with great skepticism regarding human application in the 1990s. Some of the major discoveries in the field were made by Katalin Karikó, PhD, and Drew Weissman, MD, PhD, at University of Pennsylvania, including incorporation of “pseudo-bases” to reduce immune reaction to the message itself and immediate degradation. Karikó was eventually demoted in rank at UPenn for lack of grants, but is now a senior vice president at BioNTech, a German biotechnology company that was co-founded by a pair of Turkish married physicians at Mainz University. BioNTech has become a major source of mRNA research publishing more than 150 papers in the field. Their partnership with Pfizer has brought us 1 of the mRNA SARS-CoV2 vaccines. In the United States, a Harvard professor, Derrick J. Rossi, PhD, found these mRNA congeners could reprogram stem cells, and this led to founding of Moderna (“Modified RNA”), in conjunction with the Massachusetts Institute of Technology investigators and entrepreneurial funding.
It should be noted that Moderna has been a major recipient of United States’ government funding as well as private capital. Even prior to the current pandemic, it has been funded to the tune of hundreds of millions of dollars by the Defense Advanced Research Projects Agency (DARPA) to produce mRNA vaccines against diseases including Ebola, chikungunya, and Zika. In particular, a recent letter to the government has asserted the importance of National Institute of Allergy and Infectious Diseases’ mRNA-1273 as a critical part of the invention and the contributors to numerous other patents which may have been funded by taxpayers. The Public Citizen website maintains taxpayers in the United States are paying twice for these vaccines given the degree of public funding. Moderna has never published its technologies, so funding sources for particular patents are not transparent.
In any case, key findings leading to effective mRNA-based therapy include use of pseudo-bases, proper construct including the poly-A tail, and lipo-nanoparticle encapsulation. These are all critical components and detailed by Copur. The key to this approach is translocation of the artificial mRNA coding for proteins of interest to the cytoplasm, transcription by the ribosome, and protein overproduction (as in the anti-spike protein antibodies). Also, the other arm of the immune system is involved in an alternate process involving protein degradation by proteasomes; and finally, presentation of neoantigens to dendritic and T cells induce cellular immunity. These may be augmented with use of anti–PD-(L)1 antibodies as being investigated in a number of ongoing trials listed in the table in the accompanying paper.
Most important, mRNA technology has been validated and is now subject to multibillion-dollar efforts. We hope and expect to see these important advances extend from vaccination to cancer therapies in the near future.
Garde D, Saltzman J. The story of mRNA: How a once-dismissed idea became a leading technology in the Covid vaccine race. STAT. November 10, 2020. Accessed March 22, 2021. https://bit.ly/3caFHwj