The next intriguing chapter for COVID vaccine technology

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What this tells us is that the acceptance of messenger RNA technology will likely take time, but future applications could dissolve the objections we are hearing now. In some ways, the history of this technology is only just beginning, as mRNA has uses beyond vaccines that are potentially even more transformative.

Messenger RNA plays a vital role in the body: it carries instructions to make proteins that are needed to regulate our tissues and organs and keep us healthy.

The Moderna and Pfizer vaccines both use synthetic messenger RNA to tell our cells to create a similar version of the spike protein found on the coronavirus. When our cells start producing this protein, the body recognizes it as foreign and mounts an immune response against it, which explains the side effects many people experience after receiving the COVID vaccine. After that, our immune system remembers the alien invader so that it is ready to attack if it encounters it again.

The appeal of synthetic messenger RNA is that it can be programmed with instructions to make virtually any protein. Using this technology, Moderna has developed an experimental HIV vaccine that it will soon test in a early stage trial. There is also enthusiasm for harnessing technology to make better seasonal flu vaccines, like Pfizer start human testing of an mRNA influenza vaccine.

Beyond disease prevention, synthetic mRNA might be able to cure some of them – working in conjunction with other powerful biotechnology.

Since its discovery ten years ago, the gene-editing technology known as CRISPR has shown tremendous promise for the treatment of a wide range of diseases. But a major conundrum has been: how to get CRISPR’s DNA-cutting protein where you want it to go.

Two Boston-area companies, CRISPR Therapeutics and Vertex Pharmaceuticals, are trying to treat sickle cell anemia and a related blood disorder by taking patients’ blood cells from the body, modifying them in a lab, and injecting them back into the body. But this procedure is complicated and achievable for only a handful of diseases. “We’re all trying to find ways to provide genome editing tools inside your body’s organs while you’re still using those organs,” says Daniel G. Anderson, professor of chemical engineering at MIT and co- founder of CRISPR. Therapeutic.

CRISPR cannot simply be injected into a person; it needs a delivery mechanism to reach the right cells or the right organ in the body. A delivery vehicle consists of engineered viruses, but they can elicit unwanted immune responses, present safety concerns at high doses, and are expensive to manufacture.

But what if you could get the body’s own cells to make the CRISPR machinery instead – by programming mRNA to do it? Scientists are now experimenting with using mRNA to do just that. “Conceptually and logically, this makes a lot of sense,” says Thomas Cech, a distinguished professor of biochemistry at the University of Colorado, who shared the 1989 Nobel Prize in Chemistry for his findings on the properties of RNA.

The hope is that using mRNA as a vehicle to modify genes in the body with CRISPR could cure genetic diseases or even protect against common ailments like heart disease.

To be clear, COVID-19 mRNA vaccines cannot alter our DNA in any way. Messenger RNA only stays for a few days before breaking down, and the spike proteins it tells our cells to make are shed after a few weeks.

In contrast, mRNA programmed to make the CRISPR protein will cut a gene at a desired location. Cambridge-based Intellia Therapeutics is one of the companies working on this. It aims to treat a rare genetic condition called transthyretin amyloidosis which causes a build-up of a toxic protein in the liver. The processing is performed by packaging the mRNA into fatty nanoparticles. Given intravenously, mRNA travels to the liver and goes to work to make the CRISPR components. Then, after extracting the gene responsible for the disease, the CRISPR machinery fades away.

“When Mother Nature developed messenger RNA, she had one goal: impermanence,” says Fyodor Urnov, professor of molecular and cellular biology at the University of California at Berkeley and scientific director of the Innovative Genomics Institute.

Intellia has tested its experimental treatment on six patients. After a single infusion of a relatively high dose, levels of the toxic protein fell by an average of 87 percent in three of six patients. In the other three, who received a lower dose, protein was reduced by 52 percent on average. The company has yet to reveal whether these changes alleviated patients’ symptoms.

Meanwhile, another Cambridge company, Verve Therapeutics, wants to use mRNA and CRISPR to prevent heart disease in people at high risk of developing it. In monkeys, scientists at Verve have tweaked two genes found in the liver that help regulate cholesterol levels and a harmful type of fat. People with mutations in these genes have a lower risk of heart disease. The single treatment reduced cholesterol and fat levels for over a year in monkeys. The treatment has not yet been tested in people, but the company recently announced that he plans to start a clinical trial in 2022.

The fleeting quality of messenger RNA is a major draw for biotech companies looking to avoid the potential side effects of a new treatment. “You get the edit, then it all goes and you just have to edit,” says Intellia CEO John Leonard. Many other diseases could lend themselves to the unique approach of Intellia and Verve.

Maybe any negative perception of mRNA will be fleeting, like the molecule. If the technology proves that it can safely provide cures and prevent COVID-19, concerns about it could also fade.

Emily mullin is a Pittsburgh-based freelance journalist focusing on biotechnology. Follow her on Twitter @emilylmullin.



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