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."
New Device Can Detect Peanut Allergens on a Plate in 30 Seconds
People with life-threatening allergies live in constant fear of coming into contact with deadly allergens. Researchers estimate that about 32 million Americans have food allergies, with the most severe being milk, egg, peanut, tree nuts, wheat, soy, fish, and shellfish.
"It is important to understand that just several years ago, this would not have been possible."
Every three minutes, a food allergy reaction sends someone to the emergency room, and 200,000 people in the U.S. require emergency medical care each year for allergic reactions, according to Food Allergy Research and Education.
But what if there was a way you could easily detect if something you were about to eat contains any harmful allergens? Thanks to Israeli scientists, this will soon be the case — at least for peanuts. The team has been working to develop a handheld device called Allerguard, which analyzes the vapors in your meal and can detect allergens in 30 seconds.
Leapsmag spoke with the founder and CTO of Allerguard, Guy Ayal, about the groundbreaking technology, how it works, and when it will be available to purchase.
What prompted you to create this device? Do you have a personal connection with severe food allergies?
Guy Ayal: My eldest daughter's best friend suffers from a severe food allergy, and I experienced first-hand the effect it has on the person and their immediate surroundings. Most notable for me was the effect on the quality of life – the experience of living in constant fear. Everything we do at Allerguard is basically to alleviate some of that fear.
How exactly does the device work?
The device is built on two main pillars. The first is the nano-chemical stage, in which we developed specially attuned nanoparticles that selectively adhere only to the specific molecules that we are looking for. Those molecules, once bound to the nanoparticles, induce a change in their electrical behavior, which is measured and analyzed by the second main pillar -- highly advanced machine learning algorithms, which can surmise which molecules were collected, and thus whether or not peanuts (or in the future, other allergens) were detected.
It is important to understand that just several years ago, this would not have been possible, because both the nano-chemistry, and especially the entire world of machine learning, big data, and what is commonly known as AI only started to exist in the '90s, and reached applicability for handheld devices only in the past few years.
Where are you at in the development process and when will the device be available to consumers?
We have concluded the proof of concept and proof of capability phase, when we demonstrated successful detection of the minimal known clinical amount that may cause the slightest effect in the most severely allergic person – less than 1 mg of peanut (actually it is 0.7 mg). Over the next 18 months will be productization, qualification, and validation of our device, which should be ready to market in the latter half of 2021. The sensor will be available in the U.S., and after a year in Europe and Canada.
The Allerguard was made possible through recent advances in machine learning, big data, and AI.
(Courtesy)
How much will it cost?
Our target price is about $200 for the device, with a disposable SenseCard that will run for at least a full day and cost about $1. That card is for a specific allergen and will work for multiple scans in a day, not just one time.
[At a later stage, the company will have sensors for other allergens like tree nuts, eggs, and milk, and they'll develop a multi-SenseCard that works for a few allergens at once.]
Are there any other devices on the market that do something similar to Allerguard?
No other devices are even close to supplying the level of service that we promise. All known methods for allergen detection rely on sampling of the food, which is a viable solution for homogenous foodstuffs, such as a factory testing their raw ingredients, but not for something as heterogenous as an actual dish – especially not for solid allergens such as peanuts, treenuts, or sesame.
If there is a single peanut in your plate, and you sample from anywhere on that plate which is not where that peanut is located, you will find that your sample is perfectly clean – because it is. But the dish is not. That dish is a death trap for an allergic person. Allerguard is the only suggested solution that could indeed detect that peanut, no matter where in that plate it is hiding.
Anything else readers should know?
Our first-generation product will be for peanuts only. You have to understand, we are still a start-up company, and if we don't concentrate our limited resources to one specific goal, we will not be able to achieve anything at all. Once we are ready to market our first device, the peanut detector, we will be able to start the R&D for the 2nd product, which will be for another allergen – most likely tree nuts and/or sesame, but that will probably be in debate until we actually start it.
[Ed. Note: This is the fourth episode in our Moonshot series, which explores four cutting-edge scientific developments that stand to fundamentally transform our world.]
Kira Peikoff was the editor-in-chief of Leaps.org from 2017 to 2021. As a journalist, her work has appeared in The New York Times, Newsweek, Nautilus, Popular Mechanics, The New York Academy of Sciences, and other outlets. She is also the author of four suspense novels that explore controversial issues arising from scientific innovation: Living Proof, No Time to Die, Die Again Tomorrow, and Mother Knows Best. Peikoff holds a B.A. in Journalism from New York University and an M.S. in Bioethics from Columbia University. She lives in New Jersey with her husband and two young sons. Follow her on Twitter @KiraPeikoff.