But until last year, when both Pfizer and Moderna achieved Food and Drug Administration approval, becoming the first authorized vaccines that use mRNA, there were few breakthroughs to speak of.
Now, health experts say, the tide has been turned. In the next few years, scientists expect to unlock entirely new uses for mRNA, including a new line of vaccines and treatments for cancer and neurodegenerative, rare genetic and infectious diseases.
“I think we are in a revolution that no one believed would happen,” Prof. Dan Peer, vice president for R&D and head of the Laboratory of Precision Nanomedicine at the Shmunis School of Biomedicine and Cancer Research at Tel Aviv University, told The Jerusalem Post.
“Not only did mRNA prove itself to be safe and super effective, but the technology opens numerous possibilities for treating certain types of cancer, as well as rare genetic diseases and chronic viral diseases such as AIDS,” he continued. “Basically, everything is open right now.”
Scientists are jumping on the bandwagon, and fast. If two years ago there were around 30 mRNA clinical trials, today there are more than 800 – mostly in the United States, a few in Asia and Europe, Peer said.
“This is dramatic growth that I do not think we have seen with any other kinds of therapeutics before,” he said.
ALTHOUGH SCIENTISTS were enchanted by RNA, it also challenged them – mainly for two reasons. The first is that injecting it into the body as it is can elicit a dangerous immune system overreaction. The second is that RNA is unstable and prone to degradation.
To best understand RNA, it is helpful to talk about the information flow in living cells, which starts with our DNA – a blueprint of our genes. DNA is a recipe written in a language that is composed of four letters – G, A, T and C – that stand for the nucleotide bases guanine, adenine, thymine and cytosine.
“We know that DNA in principle is a relatively stable molecule, which is logical in the sense that we want to be able to store the precious jewels, the genes, that are actually the blueprint of our bodies – everything that life is all about – in a molecule that is robust and very stable and does not break down,” explained Prof. Jonathan Gershoni of the Shmunis School.
He said that DNA is stable, on the one hand, because it is composed of two strands of molecules that run antiparallel – one runs up and the other down – and they stabilize one another carefully and precisely, like a zipper when it is closed. On the other hand, because DNA, which stands for deoxyribonucleic acid, is “missing an oxygen,” it is more resilient and able to withstand various chemical reactions that would otherwise break it down.
RNA – ribonucleic acid that is made up of four letters, GAC, like DNA, but instead of T has U for uracil – has the same information as DNA but it is housed in a single-stranded, unstable molecule.
“What we are saying is that the flow of information from our genes goes from DNA to a disposable copy of RNA to be read by ribosomes to produce proteins,” Gershoni said.
About 30 years ago, scientists came up with an idea that they could inject a person with the blueprint for the protein of a virus – just the genes corresponding to the protein – and the ribosomes would recognize the viral protein as foreign and therefore mount an immune response against it.
In 1989, scientists experimented with the first DNA vaccines, but the results were mediocre, Gershoni said. Not only did the DNA not elicit a strong and long-lasting immune response, but because DNA is a stable molecule, there was a risk that it may persist in the body and reach distant sites.
So, scientists turned to RNA. But here, too, this was not without challenges. As mentioned, the first issue is that when RNA is injected into the body, it sets off an alarm, alerting the body that a foreign entity has entered, causing the immune system to attack.
If the immune system goes into overdrive, it can be deadly.
But scientists recognized that the body can discriminate good RNA from “bad” RNA – RNA that comes from invading viruses. Good RNA functions day-to-day in the natural role of translating information from our genes for the production of protein, and therefore it is important that this RNA does not trigger any immune response.
The difference between good RNA and external or foreign RNA is that the U is tagged and slightly chemically altered “in-house.”
Scientists can now alter the RNA before injecting it into a person, changing the U to a pseudo-U, making it immediately accepted by the body without triggering a violent immune response.
But the issue of RNA stability remained. Scientists had to determine how to deliver the RNA into the body in a stable fashion.
Here, they decided not to inject RNA directly into the system, but rather to package it in lipid droplets, otherwise known as lipid nanoparticles.
“We create these small nanodroplets of lipids that contain the RNA and protect it from its surroundings and make it palatable and tasty for the cells of our immune system,” Gershoni described. “So, when we inject RNA packaged in lipid nanoparticles, the macrophages take up these lipid nanoparticles and then release the RNA into the cytoplasm, where the messenger RNA molecules are met by the ribosomes and an appropriate immune response result.”
Gershoni said that because DNA vaccines were found to be not particularly effective, when Pfizer and Moderna first presented their vaccine candidates, he was not optimistic.
“However, I was wrong. It turns out delivering an RNA message as a lipid nanoparticle is very efficient for our cells and for inducing a robust, effective immune response,” Gershoni said. “The lesson learned is that RNA technology seems to be very effective in really controlling this pandemic and reducing the anxiety and ramifications of a very traumatic event last year.”
Prof. Ronit Satchi-Fainaro, a professor of physiology and pharmacology at Tel Aviv University, said that Pfizer and Moderna were able to develop their mRNA vaccines against COVID-19 so quickly because the scientific community has been experimenting with mRNA for so many years for other indications.
She said the urgency of the global pandemic infused much more money and talent into the vaccines’ development.
“They did not cut corners,” she said. “Imagine what was set aside in terms of funding clinical trials for other diseases to have all the focus on this.”
BUT ULTIMATELY, people with some of these other diseases will benefit.
For starters, Satchi-Fainaro said that the same mRNA vaccine technology could be used against other antigens.
“It could be plug and play,” she said. “The immune system is agnostic to the antigen it is induced against, be it viral, bacteria, a cancer cell or affected neuron.”
Peer, in November, published a first paper showing how he used a technology similar to that of Pfizer and Moderna to target ovarian and geoplastomoa cancer cells and genetically neutralize them, increasing overall survival rate.
Specifically, he and his team developed what is known as CRISPR-LNPs, a lipid nanoparticle-based delivery system that targets cancer cells and destroys them through genetic manipulation. The system carries a genetic mRNA that encodes for the CRISPR enzyme Cas9 that “acts as molecular scissors that cut the cells’ DNA,” a release explained back then.
“Cancer genes are responsible for the proliferation of cancer cells,” Peer said. “We want to cut those genes, so that they will not be active anymore and the cancer cells will be destroyed forever.”
But he said that the challenge has been to deliver those “scissors” into the right cells without touching healthy cells – “you don’t want to edit the genome of a healthy cell and kill it.”
The researchers placed the mRNA inside a lipid and injected it either systemically or locally into the tumor. A GPS-like system identified the cancer cells, unlocked them and destroyed them.
Glioblastoma is one of the most aggressive types of brain cancer, with a life expectancy of 15 months since diagnosis and a five-year survival rate of only 3%. Metastatic ovarian cancer is a major cause of death among women and the most lethal cancer of the female reproductive system.
The researchers demonstrated that a single treatment with CRISPR-LNPs doubled the average life expectancy of mice with glioblastoma tumors, improving their overall survival rate by about 30%. At the same time, it increased the overall survival rate by 80% in a metastatic ovarian cancer mice model.
Peer said he expects to publish a follow-up paper at the end of the month that takes his team’s work further and demonstrates how the technology can target not only a specific receptor but specific receptor conformations.
Satchi-Fainaro said that there is also progress under way using RNA interference, using the gene’s own sequence to turn it off or silence it.
“In certain cancer types, there is a protein that is overexpressed, and we want to block it,” Satchi-Fainaro said.
Even before the pandemic, there were two drugs approved for silencing developed by the company Alnylam, which has offices in the US and Europe. Those drugs are ONPATTRO, a prescription medicine for adults that treats the polyneuropathy caused by a protein misfolding disorder called hereditary ATTR (hATTR) amyloidosis, and GIVLAARI, a prescription medicine used to treat the rare genetic disease acute hepatic porphyria.
Satchi-Fainaro said that with mRNA being accepted now by the regulatory agencies, she expects more similar treatments to quickly emerge.
Prof. Shulamit Michaeli of Bar-Ilan University said she envisions mRNA vaccines being developed against malaria, from which more than two million people a year die, and many other parasitic diseases for which vaccines still do not exist.
She mentioned Zika virus and even influenza as potential next vaccine candidates.
“For so long, people refused to work with RNA because they thought it was too difficult,” Michaeli said. “The moment we know how to handle it and understand its chemistry and biology, we can make miracles, as was shown for COVID-19.”