The dramatic success of two COVID-19 vaccines in clinical trials last month marked a triumph for a previously unproven medical technology. The vaccines, one of which was authorized for emergency use by the U.S. Food and Drug Administration last week, rely on the genetic instructions known as messenger RNA (mRNA). It prompts cells to make a SARS-CoV-2 protein that trains the immune system to recognize the virus.
But long before the pandemic, mRNA tantalized pharma, promising a simple and flexible way to deliver both vaccines and drugs. One mRNA sequence might mend a damaged heart by producing a protein that stimulates blood vessel growth. Another might encode a missing enzyme to reverse a rare genetic disease. Now, the vaccine wins have created a “tsunami” of enthusiasm around the concept, says pharmaceutical scientist Gaurav Sahay of Oregon State University, Corvallis.
But mRNA medicines—especially those that replace beneficial proteins for chronic disease—have a tougher road to the clinic than vaccines. These drugs face the challenges of targeting mRNA to specific tissues and giving strong, lasting benefits without excessive side effects. Few have made it to clinical trials. “It’s not like you just put in another sequence and it will treat anything,” says Heleen Dewitte, a pharmaceutical scientist at Ghent University. Tailoring an mRNA medicine to a disease often means tweaking the structures of both the mRNA itself and the protective bubble commonly used to ferry it through body, known as a lipid nanoparticle.
For vaccines and some mRNA drugs, administration is relatively simple. After a jab in the arm, muscle cells take up mRNA and crank out a viral protein. The immune system sees the protein as foreign and produces antibodies and T cells that arm the body against future invasion. Aside from SARS-CoV-2, mRNA vaccines against rabies, Zika, cytomegalovirus, influenza, and other viruses are advancing through clinical trials.
A local injection—into muscle, under the skin, or into a tumor—can also deliver some mRNA-based therapies that harness the immune system to fight cancer. More than a dozen clinical trials are underway for such therapies, which encode tumor proteins or immune signaling molecules to help ramp up the body’s attack on cancer cells.
Message in a bottle
Although dozens of trials are testing messenger RNA to arm the immune system against viruses or cancer, only a few companies have launched small clinical trials of other therapies—such as mRNA to replace missing or defective proteins. Here are some.
|Condition||Protein encoded by mRNA||Route of administration||Sponsoring company|
|Cystic fibrosis||CFTR, which maintains fluid balance across membranes||Inhaled||Translate Bio|
|Heart failure||VEGF-A, which stimulates blood vessel growth||Epicardial injection||AstraZeneca|
|Ornithine transcarbamylase deficiency||OTC, which helps remove nitrogen from the body||Intravenous||Arcturus Therapeutics|
|Propionic acidemia||Propionyl-CoA carboxylase, needed for normal metabolism||Intravenous||Moderna|
|Transthyretin amyloidosis||Cas9, which cuts DNA to remove a defective gene||Intravenous||Intellia Therapeutics|
But many other mRNA medicines have to find their way to a specific site in the body via the bloodstream. In ornithine transcarbamylase (OTC) deficiency, for example, a missing enzyme causes a buildup of ammonia in the blood that can lead to seizures, coma, and death. To prevent this buildup, an mRNA drug must reach cells in the liver.
mRNA medicines company Arcturus Therapeutics, which aims to treat OTC deficiency, maximized the amount of its drug that ends up in the liver, in part by adjusting the size and electrical charge of its lipid nanoparticle, says company head Joseph Payne. Arcturus has completed an initial safety study in approximately 30 healthy volunteers, and this month it dosed the first of 12 planned participants who have the deficiency.
The company chose to focus on OTC deficiency in part because the liver naturally traps and accumulates particles from the bloodstream—including the therapeutic nanoparticles. Other tissues are even tougher to reach with mRNA, says James Dahlman, a biomedical engineer at the Georgia Institute of Technology. Many teams are tweaking the structure of lipid nanoparticles or adorning them with molecules that route them to a certain organ or cell type.
Dahlman’s lab and a company he co-founded, Guide Therapeutics, have developed a technique to track the trajectories of thousands of chemically unique nanoparticles in animals by tagging them with DNA “barcodes.” But figuring out the relationship between a lipid nanoparticle’s structure and its destination is “going to take a decade,” he says.
A second big difference between vaccines and mRNA therapeutics is that vaccines require just one or a few doses. Once the immune system is trained to attack the threat at hand, the protein produced from mRNA degrades and doesn’t need replenishment. For the most part, the mRNA drugs that have advanced into clinical trials so far are ones “where the effect of the drug outlasts the drug,” Dahlman says. That’s also true for therapies that use mRNA to encode proteins such as the enzyme Cas9, which can slice the genome to make permanent edits. CRISPR editing company Intellia Therapeutics is advancing one such mRNA-based therapy for the inherited disease transthyretin amyloidosis. The company dosed its first clinical trial participant last month.
But when repeated doses of mRNA are needed to resupply a protein over a lifetime, side effects—potentially due to the buildup of lipid nanoparticles in the body or an inflammatory response to foreign RNA—loom larger. People might accept a day or two of soreness and fever after getting a COVID-19 vaccine, says Ann Barbier, chief medical officer at the mRNA therapeutics company Translate Bio. But “if you experience this every 3 weeks or so for the rest of your life, that’s a different proposition.”
To make repeated doses more tolerable, Translate Bio and others are designing mRNA to look as natural to the body as possible and delivering it in biodegradable nanoparticles. Translate Bio’s mRNA therapy for cystic fibrosis is now in clinical testing. A single dose of the therapy revealed no serious side effects; some patients experienced fever, muscle pain, or headaches, which were short-lived and manageable, the company reported. An ongoing trial is testing multiple doses.
Improving the amount of protein the body makes from a dose of mRNA would reduce the frequency and size of doses required. One approach, Sahay says, is to enhance lipid nanoparticles’ ability to “escape” from the membranous sacs that cells use to draw them in. That way, more of the nanoparticles’ mRNA cargo gets a chance to interact with the cell’s machinery for making proteins. His team reported in February that in tests in cells, swapping in naturally occurring chemical variants of the cholesterol in lipid nanoparticles made them into better escape artists.
The race for an mRNA vaccine against COVID-19 hasn’t solved the delivery and dosing issues mRNA therapies will face, but it may have smoothed their path in other ways. For one, vaccine producers have shown it’s possible to produce billions of nanoparticles and mRNA strands in short order. Sahay’s team is still puzzling out the best lipid nanoparticles to escort mRNA to the far reaches of the body. “But the day someone figures that out, it will be transformative,” he says, because the steps to getting mRNA to the clinic “are so clearly in line now.”