After decades of heavy investment by our government and society in genetic research, we now sit at the precipice of a genetic revolution—fully eclipsing the current digital revolution. If you don’t believe me, consider how mRNA vaccine technology led to the production and clinical testing of a vaccine for a novel virus in a few months. In the same year, Dr. Jennifer Doudna was awarded the Nobel Prize in Chemistry for CRISPR-Cas9 technology for editing DNA. And, this year, we finished fully sequencing the human genome. The Bill Gates, Steve Jobs, and Elon Musks of this next revolution will likely be geneticists—for better or worse.
When DNA and mRNA were first discovered in the late 1800s, I doubt we could have imagined what technology would be possible today. Even a decade ago we knew that mRNA vaccine technology had huge potential—thanks to animal research—but we were only beginning to test it for combating cancer in humans, not viruses (see my previous article on the history of mRNA vaccines). While the COVID-19 pandemic is a humanitarian crisis with catastrophic loss of life and which continues to ravage our world, ever since, there has been an uptick in the number of mRNA therapies currently in human trials (see graph below). While we don’t yet know whether these clinical trials will lead to curing cancer, genetic diseases, or combating seemingly untenable viruses like HIV or Zika, we might be closer than we realize—especially given the efficacy of mRNA vaccines for COVID-19.
What is most apparent from this graph is that a large number of mRNA therapies for cancer have been tested since 2002, and there is almost exponential growth over the past few years for all mRNA therapies. Notably, none of the therapies in the graph above are targeting COVID-19. I specifically went through the clinicaltrials.gov database and excluded them from this graph and discussion.
The types of mRNA therapies for combating cancer have changed since the first clinical trials I could find dating back to 2002. At first, they were mostly using dendritic vaccines to target melanoma. Dendritic cells are white blood cells that are instrumental in our immune response to pathogens or with respect to elimination of cells that have gone awry. They work by presenting a tag (or antigen) that helps other cells (such as T-Cells) to identify the cancer cell for destruction. Step in mRNA technology.
There are two ways mRNA technology is used for dendritic vaccines, either pulsing the cells with mRNA from the tumor, or inserting a special mRNA into the dendritic cells to make a special tag necessary to identify a cancer cell. Sounds complicated. But this had already been figured out using cell-based studies in a dish, in conjunction with animal research in mice. In these studies from the 90s, scientists extracted the dendritic cells from the mice by taking some bone marrow—this is where the dendritic cells are made in the body. Then, they exposed these dendritic cells to the mRNA of a tumor by pulsing it (i.e., letting it rest in solution together) with mRNA or inserting the mRNA into the dendritic cells. This mRNA was then used to produce a small piece of protein that was presented on the cell’s outer membrane. The presentation of the protein “tagged” the cell for other immune system cells to secrete substances which causes them to lyse (break up) and then for other cells to “consume” the remnants (phagocytosis). A tumor was then injected into the mouse along with the modified dendritic cells. In all cases the tumors were suppressed and ~80% of the mice were tumor-free. No more cancer.
Now, in the age of the gene we’ve taken this technology a step further with personalized cancer vaccines, or PCVs. Here, scientists sequence the genome of the tumor and identify around 20 tags that they think will elicit a strong immune response. They then create an mRNA molecule that, when injected, can instruct cells to make those 20 tags. The immune system is then exposed to these tags and can launch an attack on any tumor cells with those tags. No more cancer.
If you’ve kept up with how the COVID-19 mRNA vaccine works, PCVs essentially use the same technology. This would be a huge leap in combating cancer in humans for everyone, regardless of age or type of cancer. The possibilities are staggering. And yes, PCVs are currently in clinical trials and have been since at least 2017.
Since 2020, there has been a big increase in the number of mRNA vaccines for combating viruses; 9 from 2009 to 2019 and 17 since the start of 2020 (again, excluding COVID-19 vaccines). These vaccines target everything from the untenable HIV, Zika, or Cytomegalovirus to the ordinary seasonal influenza. Wait, cytomegalovirus? I had no idea what this was, and was surprised to learn that over half of adults are infected with it by the age of 40, and it is the #1 cause of infectious birth defects in the United States. While most people are asymptomatic, it is something pregnant or immunocompromised people should be protected from.
Historically untenable viruses like HIV or Zika have been problematic for human life for a number of decades as we cannot seem to create an effective vaccine. In fact there are 934 clinical trials that are active, recruiting, or enrolling people right now to learn how to better fight HIV with risk reduction and drugs. Meanwhile, ~500 clinical trials testing vaccines for HIV have been completed. This is a very serious disease that scientists have been very seriously working on for many years. Thanks to mRNA technology there is now a new option for creating vaccines against HIV, but we will just have to wait to hear the final report on the clinical trial. There is still hope.
I won’t spend anymore time on viruses, because there is honestly a plethora of information out there, done by people with more resources and background on the topic.
Currently there are a range of genetic diseases that mRNA therapies are targeting, and it was only recently that we started testing them in clinical trials. For example, current therapies target methylmalonic acidemia, glycogen storage disease, familial hypercholesterolemia, or chronic granulomatous disease. In general terms, these therapies use an I.V. infusion of mRNA to instruct the body to restore the missing or dysfunctional proteins responsible for the disease.
Methylmalonic acidemia (MMA), for example, is a rare and life-threatening metabolic disorder and is commonly caused by a deficiency in a mitochondrial enzyme called methylmalonic CoA mutase, or MUT, which can lead to toxic build up of acids in the body. Currently there are no approved therapies for the disease and the only treatment is a liver or combined liver and kidney transplant. The mRNA therapy for MMA instructs the body to make MUT, thereby providing a therapy without the need for a liver transplant.
We know that this technology is possible because of other work in cancer and viruses, but also from animal research specifically testing this therapy. Here, scientists administered the mRNA therapy through I.V. infusion to genetically engineered MMA mice that did not have the MUT enzyme. They found, as expected, that the mRNA therapy allowed the mice to make MUT protein and subsequently lower the toxic acid in the body. Repeated therapy dramatically improved the health and lifespan of the mice.
At the moment we are just in the early stages of clinical trials with mRNA therapies targeting genetic diseases. We will just have to be patient to see where it goes, and what other diseases scientists may come up with—there’s been recent buzz of using mRNA designer drugs to stimulate heart regeneration.
To close, mRNA therapies aren’t just for targeting novel viruses like COVID-19. For decades, scientists have been using them to develop therapies for other untenable viruses like HIV and Zika, as well as cancers, genetic diseases, and even heart disease. Surprisingly, the majority of therapies in human trials are targeting cancer. All this is only possible because of the government and private organizations funding work with genetics and animal research. If the speed of developing an effective COVID-19 vaccine is any indication of our future with mRNA therapies, we might just be living in a very fortunate time.
Justin A. Varholick, Ph.D.
All the data collected for this article can be found in my public github: https://github.com/javarhol/mRNA-therapy-history-data