How mRNA Could Revolutionize Medicine
In November 2020, messenger RNA catapulted into the public consciousness when the first COVID-19 vaccines were authorized for emergency use. Around the same time, an equally groundbreaking yet relatively unheralded application of mRNA technology was taking place at a London hospital.
Over the past two decades, there's been increasing interest in harnessing mRNA — molecules present in all of our cells that act like digital tape recorders, copying instructions from DNA in the cell nucleus and carrying them to the protein-making structures — to create a whole new class of therapeutics.
Scientists realized that artificial mRNA, designed in the lab, could be used to instruct our cells to produce certain antibodies, turning our bodies into vaccine-making factories, or to recognize and attack tumors. More recently, researchers recognized that mRNA could also be used to make another groundbreaking technology far more accessible to more patients: gene editing. The gene-editing tool CRISPR has generated plenty of hype for its potential to cure inherited diseases. But delivering CRISPR to the body is complicated and costly.
"Most gene editing involves taking cells out of the patient, treating them and then giving them back, which is an extremely expensive process," explains Drew Weissman, professor of medicine at the University of Pennsylvania, who was involved in developing the mRNA technology behind the COVID-19 vaccines.
But last November, a Massachusetts-based biotech company called Intellia Therapeutics showed it was possible to use mRNA to make the CRISPR system inside the body, eliminating the need to extract cells out of the body and edit them in a lab. Just as mRNA can instruct our cells to produce antibodies against a viral infection, it can also teach them to produce one of the two components that make up CRISPR — a cutting protein that snips out a problem gene.
"The pandemic has really shown that not only are mRNA approaches viable, they could in certain circumstances be vastly superior to more traditional technologies."
In Intellia's London-based clinical trial, the company applied this for the first time in a patient with a rare inherited liver disease known as hereditary transthyretin amyloidosis with polyneuropathy. The disease causes a toxic protein to build up in a person's organs and is typically fatal. In a company press release, Intellia's president and CEO John Leonard swiftly declared that its mRNA-based CRISPR therapy could usher in a "new era of potential genome editing cures."
Weissman predicts that turning CRISPR into an affordable therapy will become the next major frontier for mRNA over the coming decade. His lab is currently working on an mRNA-based CRISPR treatment for sickle cell disease. More than 300,000 babies are born with sickle cell every year, mainly in lower income nations.
"There is a FDA-approved cure, but it involves taking the bone marrow out of the person, and then giving it back which is prohibitively expensive," he says. It also requires a patient to have a matched bone marrow done. "We give an intravenous injection of mRNA lipid nanoparticles that target CRISPR to the bone marrow stem cells in the patient, which is easy, and much less expensive."
Cancer Immunotherapy
Meanwhile, the overwhelming success of the COVID-19 vaccines has focused attention on other ways of using mRNA to bolster the immune system against threats ranging from other infectious diseases to cancer.
The practicality of mRNA vaccines – relatively small quantities are required to induce an antibody response – coupled with their adaptable design, mean companies like Moderna are now targeting pathogens like Zika, chikungunya and cytomegalovirus, or CMV, which previously considered commercially unviable for vaccine developers. This is because outbreaks have been relatively sporadic, and these viruses mainly affect people in low-income nations who can't afford to pay premium prices for a vaccine. But mRNA technology means that jabs could be produced on a flexible basis, when required, at relatively low cost.
Other scientists suggest that mRNA could even provide a means of developing a universal influenza vaccine, a goal that's long been the Holy Grail for vaccinologists around the world.
"The mRNA technology allows you to pick out bits of the virus that you want to induce immunity to," says Michael Mulqueen, vice president of business development at eTheRNA, a Belgium-based biotech that's developing mRNA-based vaccines for malaria and HIV, as well as various forms of cancer. "This means you can get the immune system primed to the bits of the virus that don't vary so much between strains. So you could actually have a single vaccine that protects against a whole raft of different variants of the same virus, offering more universal coverage."
Before mRNA became synonymous with vaccines, its biggest potential was for cancer treatments. BioNTech, the German biotech company that collaborated with Pfizer to develop the first authorized COVID-19 vaccine, was initially founded to utilize mRNA for personalized cancer treatments, and the company remains interested in cancers ranging from melanoma to breast cancer.
One of the major hurdles in treating cancer has been the fact that tumors can look very different from one person to the next. It's why conventional approaches, such as chemotherapy or radiation, don't work for every patient. But weaponizing mRNA against cancer primes the immune cells with the tumor's specific genetic sequence, training the patient's body to attack their own unique type of cancer.
"It means you're able to think about personalizing cancer treatments down to specific subgroups of patients," says Mulqueen. "For example, eTheRNA are developing a renal cell carcinoma treatment which will be targeted at around 20% of these patients, who have specific tumor types. We're hoping to take that to human trials next year, but the challenge is trying to identify the right patients for the treatment at an early stage."
Repairing Damaged mRNA
While hopes are high that mRNA could usher in new cancer treatments and make CRISPR more accessible, a growing number of companies are also exploring an alternative to gene editing, known as RNA editing.
In genetic disorders, the mRNA in certain cells is impaired due to a rogue gene defect, and so the body ceases to produce a particular vital protein. Instead of permanently deleting the problem gene with CRISPR, the idea behind RNA editing is to inject small pieces of synthetic mRNA to repair the existing mRNA. Scientists think this approach will allow normal protein production to resume.
Over the past few years, this approach has gathered momentum, as some researchers have recognized that it holds certain key advantages over CRISPR. Companies from Belgium to Japan are now looking at RNA editing to treat all kinds of disorders, from Huntingdon's disease, to amyotrophic lateral sclerosis, or ALS, and certain types of cancer.
"With RNA editing, you don't need to make any changes to the DNA," explains Daniel de Boer, CEO of Dutch biotech ProQR, which is looking to treat rare genetic disorders that cause blindness. "Changes to the DNA are permanent, so if something goes wrong, that may not be desirable. With RNA editing, it's a temporary change, so we dose patients with our drugs once or twice a year."
Last month, ProQR reported a landmark case study, in which a patient with a rare form of blindness called Leber congenital amaurosis, which affects the retina at the back of the eye, recovered vision after three months of treatment.
"We have seen that this RNA therapy restores vision in people that were completely blind for a year or so," says de Boer. "They were able to see again, to read again. We think there are a large number of other genetic diseases we could go after with this technology. There are thousands of different mutations that can lead to blindness, and we think this technology can target approximately 25% of them."
Ultimately, there's likely to be a role for both RNA editing and CRISPR, depending on the disease. "I think CRISPR is ideally suited for illnesses where you would like to permanently correct a genetic defect," says Joshua Rosenthal of the Marine Biology Laboratory in Chicago. "Whereas RNA editing could be used to treat things like pain, where you might want to reset a neural circuit temporarily over a shorter period of time."
Much of this research has been accelerated by the COVID-19 pandemic, which has played a major role in bringing mRNA to the forefront of people's minds as a therapeutic.
"The pandemic has really shown that not only are mRNA approaches viable, they could in certain circumstances be vastly superior to more traditional technologies," says Mulqueen. "In the future, I would not be surprised if many of the top pharma products are mRNA derived."
Kids' immune systems come into contact with so many antigens every day that extra cleaning and disinfecting won't harm them, experts say.
Cleaning has taken on a whole new meaning in Frank Mosco's household during the COVID-19 pandemic. There's a protocol for everything he and his two teenage daughters do.
Experts agree that over-disinfecting is better than inadequate disinfecting, especially during a pandemic.
"We wipe down every package that comes into the house and the items inside," says Mosco, a technologist and social justice activist in Hastings-on-Hudson, N.Y. "If it's a fruit or vegetable, I use vinegar and water, or water and soap. Then we throw out the boxes, clean up the table, and wash our hands." Only then do they put items away.
As the novel coronavirus continues to pose an invisible threat, parents of infants to adolescents are pondering how vigorously and frequently to clean and disinfect surfaces at home and apply hand sanitizer in public. They also fret over whether there can be too much of a good thing: Will making everything as seemingly germ-free as possible reduce immunity down the road?
Experts agree that over-disinfecting is better than inadequate disinfecting, especially during a pandemic. Every family should assess their particular risks. Factors to consider include pre-existing medical conditions, the number of people living in the same home, and whether anyone works in a hospital or other virus-prone environment, says Kari Debbink, assistant professor of biology at Bowie State University in Bowie, Maryland.
Constantly cleaning everything in sight isn't necessary, she explains, because coronavirus tends to spread mainly via immediate contact with respiratory droplets—catching it from surfaces is a less-likely scenario. The longer the virus stays on a surface, the less contagious it becomes.
Some parents worry that their children's growing bodies may become accustomed to an environment that is "too clean." Debbink, a virologist, offers a salient reminder: "The immune system comes into contact with many, many different antigens every day, and it is 'trained' from birth onwards to respond to pathogens. Doing a little more cleansing and disinfecting during the pandemic will not weaken the immune system."
Other experts agree. "There should be no negative outcome to properly washing your hands more frequently," says Stacey Schultz-Cherry, an infectious diseases specialist at St. Jude Children's Research Hospital in Memphis, Tennessee. "Even with enhanced disinfection, kids are still getting exposed to immune-boosting microbes from playing outside, having pets, etc."
"There's no reason why hand sanitizer would weaken anyone's immune system of any age."
Applying hand sanitizer consisting of at least 60 percent alcohol helps clean hands while outdoors, says Angela Rasmussen, associate research scientist and a virologist at Columbia University's Mailman School of Public Health in New York. "There's no reason why hand sanitizer would weaken anyone's immune system of any age," she adds, and recommends moisturizer so hands don't dry out from frequent use. Meanwhile, "cleaning and disinfecting at home also don't have an impact on antiviral immunity, in kids or adults."
With the coronavirus foremost in parents' minds, Patricia Garcia, a pediatric hospitalist, has fielded many questions about how thoroughly they should wipe, rub, scrub, or mop. As medical director of Connecticut Children's Healthy Homes Program in Hartford, which takes aim at toxins and other housing hazards, she reassures them with this mantra: "You're never going to get it perfectly sterilized, and that's okay."
To quell some of these concerns, in March the U.S. Environmental Protection Agency (EPA) released a list of products for household use. None of these products have been specifically tested against SARS-CoV-2, the novel coronavirus that causes COVID-19. But the agency expects these products to be effective because they have demonstrated efficacy against a different human coronavirus similar to SARS-CoV-2 or an even harder-to-kill virus.
Many products on the list contain isopropyl alcohol or hydrogen peroxide. "When using an EPA-registered disinfectant," the agency's website instructs, "follow the label directions for safe, effective use. Make sure to follow the contact time, which is the amount of time the surface should be visibly wet."
Bear in mind that not all cleaners actually disinfect, cautions Alan Woolf, a pediatrician at Boston Children's Hospital who directs its environmental health center and is a professor at Harvard Medical School. Some cleaners remove visible dirt, grease, and grime, but they don't kill viruses. Disinfectants by their nature inactivate both bacteria and viruses. "That's an important distinction," Woolf says.
Frequently touched surfaces—for instance, doorknobs, light switches, toilet-flushing levers, and countertops—should not only be cleaned, but also disinfected at least daily during a pandemic if someone in the household is sick. The objects one touches upon coming home are the ones most likely to become contaminated with viruses, experts say.
Before bringing items inside, "it might be good to clear off a counter space where they will be placed," says Debbink, the biology professor and virologist. "This way, they come into contact with as few items and surfaces as possible."
If space permits, another option would be to set aside nonperishable items. "I've heard of some families putting things in a 'mud room' and closing the door for 48 hours, some leaving things in their garage or car trunk," says Stephanie Holm, co-director of the Western States Pediatric Environmental Health Specialty Unit at the University of California, San Francisco. "Letting new purchases sit for 48 hours undisturbed would greatly reduce the number of viable viruses present."
Cleaning surfaces is recommended before disinfecting them. Holm suggests using unscented soap and microfiber cloths instead of paper towels, which can transmit bacteria and viruses from one area to another.
Soap has the power to eradicate viruses with at least 20 seconds of contact time. It attacks the coronavirus's protective coat, explains infectious diseases specialist Schultz-Cherry. "If you destroy the coat, the virus is no longer infectious. Influenza virus is also very sensitive to soap."
"The most important thing that parents should do for children's immune systems is make sure they are up to date on all their vaccines."
For cribs, toys, and other mouth-contact surfaces, sanitizing with soap and water, not disinfectants, is advisable, says pediatrician Woolf. Fresh fruits and vegetables also can be cleaned with soap, removing dirt and pesticide residue, he adds.
"Some parents are nervous about using disinfectant on toys, which is understandable, considering many toys end up in children's mouths, so soap and water can be an alternative," says pediatrician Garcia, who recommends using hot water.
While some toys can go in the washing machine and dryer or dishwasher, others need to be cleaned by hand, with dish soap or a delicate detergent, as indicated on their labels. But toys with electrical components cannot be submerged in water, in which case consulting the EPA's list of disinfectants may be a parent's best option, she says.
Labels on the back of cleaning and disinfecting products also contain specific instructions. Not allowing a liquid to sit on a surface for the recommended time results in exposure to chemicals without even accomplishing the intended purpose of disinfection. For most household bleach-containing agents, the advisable "dwell time" is 10 minutes. "Many people don't realize this," says Holm, the environmental health specialist who also trained as a physician.
Beware of combining any type of cleaners or disinfectants that aren't already premixed. Doing so can release harmful gases into the air, she cautions.
During the pandemic, Mosco and his daughters have been very conscientious about decontaminating whatever comes through their doors. Mosco says he doesn't believe the family is overusing cleaning and disinfecting products. Although he's fastidious, he says, "a completely sterile environment is not the goal."
His mother, who was a nurse, instilled in him that exposure to some bacteria is a good thing. In turn, he "always encouraged his kids to play with animals, and to have fun in sand and dirt, with plenty of sunlight to keep their immune systems strong."
Even though a vaccine for coronavirus currently doesn't exist, parents can take some comfort in the best weapon available today to protect kids from deadly pathogens: "The most important thing that parents should do for children's immune systems," says virologist Rasmussen, "is make sure they are up to date on all their vaccines."
A researcher works in the lab at Alnylam Pharmaceuticals, which has pioneered the development of RNAi therapies.
In October 2006, Craig Mello received a strange phone call from Sweden at 4:30 a.m. The voice at the other end of the line told him to get dressed and that his life was about to change.
"We think this could be effective in [the early] phase, helping the body clear the virus and preventing progression to that severe hyperimmune response which occurs in some patients."
Shortly afterwards, he was informed that along with his colleague Andrew Fire, he had won the Nobel Prize in Physiology or Medicine.
Eight years earlier, biologists Fire and Mello had made a landmark discovery in the history of genetics. In a series of experiments conducted in worms, they had revealed an ancient evolutionary mechanism present in all animals that allows RNA – the structures within our cells that take genetic information from DNA and use it to make proteins – to selectively switch off genes.
At the time, scientists heralded the dawn of a new field of medical research utilizing this mechanism, known as RNA interference or RNAi, to tackle rare genetic diseases and deactivate viruses. Now, 14 years later, the pharmaceutical company Alnylam — which has pioneered the development of RNAi-based treatments over the past decade — is looking to use it to develop a groundbreaking drug for the virus that causes COVID-19.
"We can design small interfering RNAs to target regions of the viral genome and bind to them," said Akin Akinc, who manages several of Alnylam's drug development programs. "What we're learning about COVID-19 is that there's an early phase where there's lots of viral replication and a high viral load. We think this could be effective in that phase, helping the body clear the virus and preventing progression to that severe hyperimmune response which occurs in some patients."
Called ALN-COV, Alnylam's treatment hypothetically works by switching off a key gene in the virus, inhibiting its ability to replicate itself. In order to deliver it to the epithelial cells deep in the lung tissue, where the virus resides, patients will inhale a fine mist containing the RNAi molecules mixed in a saline solution, using a nebulizer.
But before human trials of the drug can begin, the company needs to convince regulators that it is both safe and effective in a series of preclinical trials. While early results appear promising - when mixed with the virus in a test tube, the drug displayed a 95 percent inhibition rate – experts are reserving judgment until it performs in clinical trials.
"If successful this could be a very important milestone in the development of RNAi therapies, but virus infections are very complicated and it can be hard to predict whether a given level of inhibition in cell culture will be sufficient to have a significant impact on the course of the infection," said Si-Ping Han, who researches RNAi therapeutics at California Institute of Technology and is not involved in the development of this drug.
So far, Alnylam has had success in using RNAi to treat rare genetic diseases. It currently has treatments licensed for Hereditary ATTR Amyloidosis and Acute Hepatic Porphyria. Another treatment, for Primary Hyperoxaluria Type 1, is currently under regulatory review. But its only previous attempt to use RNAi to tackle a respiratory infection was a failed effort to develop a drug for respiratory syncytial virus (RSV) almost a decade ago.
However, the technology has advanced considerably since then. "Back then, RNAi drugs had no chemical modifications whatsoever, so they were readily degraded by the body, and they could also result in unintended immune stimulation," said Akinc. "Since then, we've learned how to chemically modify our RNAi's to make them immunosilent and give them improved potency, stability, and duration of action."
"It would be a very important milestone in the development of RNAi therapies."
But one key challenge the company will face is the sheer speed at which viruses evolve, meaning they can become drug-resistant very quickly. Scientists predict that Alnylam will ultimately have to develop a series of RNAi drugs for the coronavirus that work together.
"There's been considerable interest in using RNAi to treat viral infections, as RNA therapies can be developed more rapidly than protein therapies like monoclonal antibodies, since one only needs to know the viral genome sequence to begin to design them," said David Schaffer, professor of bioengineering at University of California, Berkeley. "But viruses can evolve their sequences rapidly around single drugs so it is likely that a combinatorial RNAi therapy may be needed."
In the meantime, Alnylam is conducting further preclinical trials over the summer and fall, with the aim of launching testing in human volunteers by the end of this year -- an ambitious aim that would represent a breakneck pace for a drug development program.
If the approach does ultimately succeed, it would represent a major breakthrough for the field as a whole, potentially opening the door to a whole new wave of RNAi treatments for different lung infections and diseases.
"It would be a very important milestone in the development of RNAi therapies," said Han, the Caltech researcher. "It would be both the first time that an RNAi drug has been successfully used to treat a respiratory infection and as far as I know, the first time that one has been successful in treating any disease in the lungs. RNAi is a platform that can be reconfigured to hit different targets, and so once the first drug has been developed, we can expect a rapid flow of variants targeting other respiratory infections or other lung diseases."