UMass Amherst researchers are developing technology to make extremely pure and plentiful RNA that could enable a new class of vaccines and treatments for a range of deadly diseases, according to a news release from the university.
In December 2020, less than a year after the novel coronavirus was initially sequenced, Americans began receiving the first doses of the COVID-19 vaccine. Despite the rocky road ahead — paved with vaccine hesitancy and misinformation, uneven vaccination rollouts around the world, new variants and diminishing immunity over time — the rapid development of vaccines to protect against serious illness and death. It showed the world what many scientists have believed for decades; that a new class of mRNA drugs could transform medicine.
Yet, the COVID-19 vaccines are only the beginning. Like other scientists, Craig Martin, Professor of Chemistry at the University of Massachusetts Amherst, believes there is enormous potential in mRNA for both vaccines and therapeutics more broadly. Together with collaborators in UMass Amherst’s Department of Chemical Engineering, Martin is developing a new manufacturing process for RNA that promises to remove the key barriers that constrain its use in treating and preventing disease today. This, he said, would open doors to everything from personalized cancer treatments to better therapies for genetic disorders like Tay-Sachs and cystic fibrosis, to the ability to quickly and inexpensively develop vaccines that could be deployed around the globe against the next pathogen to threaten public health.
Once you know how to make the RNA for one disease, it’s comparatively easy to swap in a different RNA so it can treat another disease. You don’t have to reinvent the wheel, saving money, and crucially saving time.
The promise of mRNA
There’s a growing belief in the scientific community that mRNA (short for messenger RNA) could be the future of medicine. Traditionally, illnesses have been treated by medicines that come from outside the human body, such as herbs, chemicals, and vaccines. Recently, a new approach has emerged called biologics—including gene replacement therapies used to treat a wide range of illnesses by delivering proteins to the body that are missing or damaged. “In general, biologics harness the power of biology to offer exquisite specificity,” said Martin.
But this process can be taken one step further, as has been demonstrated with the COVID-19 mRNA vaccines. “Instead of making the protein in some other organism and delivering it to humans, we can make the RNA that encodes the protein, deliver that RNA as the biologic, and the patient’s own cells then make that protein from the delivered RNA,” Martin explained. When the patient’s own cells make the protein, it eliminates room for error. Moreover, “Once you know how to make the RNA for one disease, it’s comparatively easy to swap in a different RNA so it can treat another disease. You don’t have to reinvent the wheel, saving money, and crucially — saving time,” he said.
However, a key sticking point is making RNA that is pure enough and in large enough quantities. Traditionally, labs produce RNA in a batch process, which — when done at the scale needed for therapeutics — tends to yield a biproduct called double-stranded RNA. When the human body encounters double-stranded RNA, it triggers an innate immune response causing inflammation, such as the types of side effects often experienced after a vaccination. In the case of vaccines, a little bit of an immune reaction is okay, Martin explained, because the purpose of vaccines is to prime the body’s immune system to recognize disease. But for therapeutics to treat a condition like cystic fibrosis, this kind of inflammation could be deadly. Lab-produced RNA can be purified, but it is complicated and costly to do so.
For more than 30 years, Martin’s lab has studied the chemical mechanisms of RNA polymerase, an enzyme that controls the process of transcription; in which information from DNA is copied into a new molecule of mRNA. Several years ago, it pivoted to improving the process of RNA manufacturing to avoid the impurities from the start. Rather than using a traditional batch reactor to produce RNA — in which the components are mixed and sit for several hours — they wanted to create a flow reactor to enable chemical reactions in continuous, flowing systems. “The main benefit of this approach is that the RNA never sits around the enzyme for too long, preventing the secondary reaction,” that causes the impurity, said Martin.
Martin is optimistic that he and his fellow researchers can advance RNA manufacturing enough to have a real impact on the next global health crisis. Beyond that, he is excited about the potential of mRNA to transform the way we treat a wide range of diseases. While vaccinating a large population against a new pathogen will require a massive scaling up of mRNA manufacturing, treating genetic disorders, rare or “orphan” diseases, or deploying personalized cancer vaccines may involve scaling down production in order to produce a very small amount of customized RNA to treat each patient.
For example, today metastatic cancer is extremely difficult to treat with drugs because it is caused by the body’s own cells growing uncontrollably. A personalized cancer therapy could be developed by sequencing the genome of an individual’s normal cells and cancer cells to identify the mutation in the cancer cells, then using an RNA-based therapy to train the body to mount an immune response to just the cancer cells.
Martin said such innovative treatment approaches are already being developed by pharmaceutical companies but have been largely “waiting in the wings” due to a lack of access to sufficiently pure RNA.
“If we’re able to achieve what I think we can with this new technology to produce RNA, I’m optimistic that more companies will begin to take these treatments off the shelves and bring them forward to clinical trials,” said Martin.