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Messenger RNAs—molecules that carry information between the genome and the protein-building machinery of cells—could become the next big class of biopharmaceutical drug.

These molecules were once thought unusable as drugs because they are notoriously fragile and could rouse an inflammatory immune response. Now, thanks to several recent scientific discoveries, they are attracting the increasing attention of pharmaceutical companies.

Recently, the pharmaceutical heavyweight AstraZeneca announced it would pay Moderna Therapetuics $240 million for rights to the startup’s mRNA technology, which it will use to develop treatments for cardiovascular, metabolic, and cancer patients.

Inside a cell, mRNA serves as an intermediary between DNA-encoding genes and their protein products. As a drug, an mRNA would supply the biological instructions for producing a protein inside cells, perhaps a protein that replaces a missing or broken version inherited as part of a genetic disorder. In some ways, an mRNA would be more efficient than DNA-based gene therapy (which would require the cells to make their own mRNA intermediary before producing a protein) and more effective than recombinant protein therapy. While several companies are developing therapeutic gene-silencing RNAs, which inhibit damaging proteins from being made in the body (see “RNAi Drug for Cholesterol” and “Gene Silencing Technique Targets Scarring”), few have tried adapting mRNAs to bring in beneficial replacement gene products.

One reason is that natural mRNAs stir up trouble in the body. “If you inject regular mRNA into the body, the body thinks it’s a virus, so you get a very strong innate immune response,” says Stephane Bancel, CEO of Moderna, based in Cambridge, Massachusetts. To avoid this reaction, Moderna changes some of the building blocks of its mRNAs, known as nucleotides, so that the immune system no longer recognizes the molecule as dangerous. Of the four possible nucleotide “letters” in an mRNA, the company uses one or two variants or analogs of the standard nucleotides when synthesizing its mRNA. These analogs exist naturally in cells, but the idea that subbing them into mRNA sequences could avoid an immune system response is only a few years old—it was first reported by University of Pennsylvania School of Medicine researchers in 2005.

The substitutions seem to help another hangup with mRNAs—their notorious fragility. “Everybody considers mRNA to be the most unstable molecule you can think of,” says Christian Plank, founder and chief scientific officer of Ethris, a German company also developing modified mRNAs as drugs. “This opinion is still in the minds of most people and is a major reason why only a few people have thought of using it,” says Plank.

The analogs make the mRNAs more stable, and the company has shown that the molecules can last for up to 72 hours in the body, says Bancel. In comparison, some protein therapies can be gone within a few hours, he says.

Once injected, the mRNA is taken up by cells, says Bancel. The cell’s machinery then reads the mRNA and produces whatever protein it encodes. “The beauty is that the patient’s cells produce the drug,” says Carsten Rudolph, CEO of Ethris. That means that the proteins made from an injected mRNA would carry less of an immune response risk than if the proteins were made in bacteria or yeast and then injected, says Rudolph. And more proteins may then be available to patients, because not every protein can be manufactured at large scale.

Finally, mRNAs cannot integrate into the genome and so do not present the same risk of disrupting normal gene that DNA-based gene therapies do. “In general, gene therapy is a good approach, and in recent years there have been good breakthroughs, but for non-life-threatening disease, you want to avoid any potential risk you can think of, and integration into the genome is a known risk,” says Plank.

Ethris also recently partnered with a pharmaceutical companyShire, based in Massachusetts—to develop treatments for patients with rare diseases based on its technology. Success for either AstraZeneca or Shire will require a venture into still uncharted waters: the first in-patient studies of the new biopharmaceutical.

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Tagged: Biomedicine, Business, gene therapy, Stéphane Bancel

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