Feb. 9, 2021 -- The Pfizer and Moderna COVID-19 vaccines have put mRNA technology on the map, providing real-world proof that this emerging branch of medicine offers a viable way to save lives by preventing emerging infectious diseases.
Now, scientists and researchers are looking to harness mRNA for a tantalizingly greater purpose: treating chronic illnesses.
Over the past decade, mRNA -- short for messenger ribonucleic acid -- has emerged as a promising next-generation technology for creating a new class of medications to treat cystic fibrosis, heart disease, rare genetic conditions, and even some cancers.
Many scientific and regulatory hurdles lie ahead for these new mRNA-based therapies, which are likely to be more complicated to develop than the COVID-19 vaccines.
But the safety and effectiveness of the new vaccines, and the breakneck speed at which they were developed, have spotlighted the potential for other medicinal uses of mRNA. And the future looks promising, experts say.
“Now that they’ve been able to prove their worth with such high efficacy against COVID-19, you’re going to see mRNA vaccines flourish when it comes to thinking about other disease threats,” says Amesh Adalja, MD, an emerging infectious disease specialist with the Johns Hopkins Center for Health Security.
“I think you’re going to see probably a twofold impact with mRNA -- one in preventive vaccines for other emerging infectious diseases as well as therapeutic vaccines they’re looking at, for cancer, for example ... and other lifestyle diseases and chronic diseases.”
That mRNA shift -- from prevention to treatment -- is already underway. For instance:
- Moderna has more than two dozen prospective mRNA therapies and vaccines in the pipeline -- some in partnership with Big Pharma heavy hitters like Merck and AstraZeneca -- targeting genetic diseases, influenza, HIV, heart disease, and cancer.
- BioNTech has a similar number of new mRNA studies and research projects in the works for various cancers, tuberculosis, and the flu.
- And CureVac, another leading mRNA biotech company, has launched studies into a half-dozen other potential medical uses.
Moderna President Stephen Hoge, MD, says mRNA holds such promise as a therapeutic agent because it is what he calls “the software of life.”
Cells use mRNA to translate the genes of DNA into dynamic proteins, involved in virtually every bodily function and health condition. Biotech companies make some of these proteins as drugs, using genetically engineered cells in factories. But, in theory, mRNA therapies may be used to prompt proteins to be made in your body -- in effect putting the drug factory inside you, Hoge says.
“You could ultimately use mRNA to express any protein and perhaps treat almost any disease,” Hoge said in a recent interview with C&EN. “It is almost limitless what it can do.”
One major focus of Moderna is the development of novel “cancer vaccines” tailored to individual patients that amp up their natural immune defenses, often in combination with other immunotherapy drugs. Unlike traditional vaccines, which are typically used to prevent diseases, these new vaccines are used to treat illnesses.
Game Changer for the Drug Industry?
If mRNA therapeutics prove to be as successful as the COVID-19 vaccines, mRNA could transform the drug industry, just as biotech companies like Biogen and Genentech developed protein therapies called biologics in the 1980s.
Those therapies are now the fastest-growing segment of the drug industry, and some experts have suggested mRNA could overtake them.
The early evidence looks promising, and the COVID-19 vaccines have provided a gateway that seems likely to accelerate mRNA research and development.
For instance, BioNTech, Pfizer’s COVID-19 vaccine partner, recently released a new study showing mRNA might work to combat multiple sclerosis.
The research led by BioNTech’s CEO, Ugur Sahin, MD, found that an mRNA vaccine significantly eased symptoms in mice engineered to develop a rodent form of MS. The study, published in Science, also found that the vaccine prevented the disease’s progression.
The therapeutic vaccine contained genetic information coding for MS-causing antigens, modeled after the approach used in the COVID-19 shots -- providing another proof-of-concept endorsement for the technology.
Setbacks on the Path to Advancement
But there are caveats. Not all of the recent news on mRNA has been positive.
First of all, none of the mRNA therapies under study have been conclusively validated in clinical trials for safety and effectiveness in the way the Pfizer and Moderna COVID-19 vaccines have.
Secondly, the FDA has yet to greenlight any of these treatments.
What’s more, some early trials of mRNA therapies have suffered major stumbling blocks on the road to market approval.
In January, CureVac reported disappointing results in a clinical trial of its new mRNA-based drug for prostate cancer. The company’s CV9014 drug did not boost the survival rates of men with metastatic prostate cancer or halt the disease’s progression, the two primary goals of the study.
CureVac founder Ingmar Hoerr, PhD, called the findings a temporary setback, noting CV9014 was shown to be safe and preclinical testing suggests it might prove effective if used with other immunotherapy drugs known as checkpoint inhibitors. These drugs, such as Merck’s Keytruda, Bristol-Myers Squibb’s Opdivo, and Roche’s Tecentriq, were not on the market when the CV9014 study began.
“We’re already planning with our partner, Boehringer Ingelheim, to start clinical trials of mRNA in combination with checkpoint inhibitors,” Hoerr told the European publication Labiotech.
The two companies are also partnering on another prospective mRNA vaccine for lung cancer.
But the setback for CureVac, which has been backed by Microsoft co-founder Bill Gates and German entrepreneur Dietmar Hopp, among others, is a reminder that mRNA faces significant hurdles as a therapeutic.
That’s particularly true when it comes to creating new treatments for the thousands of different types of cancer, each of which has its own set of challenges.
Maurie Markman, MD, says mRNA therapy holds promise. But he urges caution along with the optimism generated by the Moderna and Pfizer COVID-19 vaccines.
“The treatment of cancer is a different universe than preventing cancer through innovation,” notes Markman, president of medicine and science at the Cancer Treatment Centers of America.
“Unfortunately, we’re wrapped up in simple terms like RNA, DNA and vaccines, and we say, ‘Well, if we can treat one group of diseases, including viruses, and we are successful in this area, can’t we take the same technology, the same strategy, and work on another disease? And the answer is: Absolutely we should look, but to assume that we’re looking at things that are comparable is problematic.”
MRNA at a Glance
What is mRNA, and how does it work its medicinal magic?
Today, the formerly obscure term is ubiquitous, thanks to the barrage of news about the coronavirus pandemic. A simple Google search for “mRNA” returns nearly 80 million links (about a third of what “Lady Gaga" fetches, by comparison).
Essentially, mRNA is a single-stranded molecule, naturally present in all of our cells. Identified in 1961, mRNA carries instructions to cells for making proteins from our genes that are used as building blocks of their fundamental structures and functions.
Without getting too technical, a segment of DNA gets copied into a piece of mRNA that gives our cells commands for making specific proteins, some of which cause or prevent disease.
The COVID-19 vaccines, for example, contain the coronavirus’s mRNA (which cannot cause infection). When injected into muscle, our cells “read” it and synthesize the non-infectious “spike protein” found on the surface of the virus.
That prompts our immune systems to create these harmless proteins and develop the tools needed to target and kill the virus if we become infected afterward.
MRNA technology is not new. Researchers have been delving into the mysteries of mRNA -- and unraveling the role it might play in disease -- for decades.
In fact, Moderna, BioNTech, and CureVac were studying the potential medical benefits of mRNA long before the COVID-19 pandemic created the opportunity to harness mRNA to create a new kind of vaccine.
The reason mRNA holds such promise is that it combats disease in an entirely different way than most drugs on the market.
Hundreds of clinical trials are in various stages of testing mRNA as a way to prevent or treat infections and chronic diseases, according to Clinicaltrials.gov, the federal clearinghouse for ongoing studies worldwide.
Among the higher-profile studies in the works:
- Moderna is partnering with Merck in a clinical trial of a combo treatment -- using a personalized mRNA cancer vaccine along with the immunotherapy drug Keytruda -- for patients with colorectal and head and neck cancers. Early results, reported last November, were promising.
- AstraZeneca is testing a new mRNA-based treatment for heart failure.
- Translate Bio Inc. is studying mRNA for cystic fibrosis.
- CRISPR editing company Intellia Therapeutics is evaluating an mRNA-based therapy for the rare inherited disease transthyretin amyloidosis.
- Other companies are looking into the potential of using mRNA to target lung, ovarian, and pancreatic cancers, among others.
'Change the Entire Approach’
In the short term, Adalja believes the real promise of mRNA will be in combating emerging infectious diseases like COVID-19 with safe and effective vaccines that can be quickly created and rolled out.
“I think that even though most people hadn’t heard about mRNA vaccine technology before now, it had been something that many of us in the field saw as a way to revolutionize the way vaccines were developed, especially vaccines that needed to be made rapidly for an emerging infectious disease outbreak,” Adalja says.
He produced a major report on new vaccine platform technologies 2 years ago that spotlighted the promise of mRNA.
“MRNA vaccines are a way to really change the entire approach to emerging infectious disease outbreaks because they are so simple to make,” he says. “Basically, all you need to know is what your pathogen is, what the target is for the immune system, and then you sequence it and make the piece of mRNA that’s necessary, and then you inject it into someone.”
But Adalja also believes mRNA technology is likely to gain ground in the world of non-infectious chronic diseases.
“It’s important to remember that a lot of the early interest in mRNA was in sequencing individual tumors and then making vaccines against those tumors. For example, a personalized lung cancer vaccine,” he says.
“So I do think that’s where you’re going to see a lot of investment in mRNA vaccines because that’s very lucrative, and that’s where we desperately need new treatment options. I’m not an oncologist, but the idea that these vaccines could be used therapeutically for cancer -- that’s something the oncology world has been pursuing.”