Big things from small places: Modified RNAs eyed as a way to make new drugs

by Nancy Fliesler on March 22, 2013

A technology from a small research institute, originally developed as a safer way to make embryonic-like stem cells, just hooked a very large fish. As The New York Times reported yesterday, pharma giant AstraZeneca is betting at least $240 million that this technology could be the source of a variety of new drugs—drugs that spur the body itself to make what it needs.

In 2010, the lab of Derrick Rossi at the Immune Disease Institute, which is now the Program in Cellular and Molecular Medicine at Boston Children’s Hospital, reported that they could reprogram ordinary cells into pluripotent stem cells by simply injecting them with messenger RNAs. The mRNAs reprogrammed the cells up to 100 percent more efficiently than other techniques, and did so without becoming part of the cell’s genome, greatly reducing concerns about cancer associated with other methods.

Key to the discovery were the chemical modifications made to the mRNAs so that cells wouldn’t “see” them as viruses and attack them. This video and this article describe the modified mRNA technique, also described in Cell Stem Cell:

As AstraZeneca recognized, these synthetic, modified mRNAs have therapeutic implications that go far beyond making stem cells. The technology is the flip side of RNA interference (RNAi), the gene-silencing technology that earned the Nobel prize in 2006. Whereas RNAi silences genes by blocking the production of abnormal or unwanted proteins, mRNAs spur cells to make proteins we want to have—adding back proteins our bodies don’t make enough of, or that don’t work as they should.

Messenger RNAs (shown in pink), modified to prevent the cell from attacking them, take instructions to the ribosomes where the desired proteins are made. The cell's DNA is unchanged. (Graham Peterson illustration)

Soon after the paper came out, Boston Children’s Hospital licensed the technology to Moderna Therapeutics in Cambridge. Moderna was cofounded by Rossi, Robert Langer, ScD, of the Massachusetts Institute of Technology, Kenneth Chien, MD, PhD, of Massachusetts General Hospital, and Flagship Ventures Labs, with investment from Flagship and angel investors. Its strategic alliance with AstraZeneca is aimed at developing mRNA therapeutics for the treatment of cancer and cardiovascular, metabolic and renal diseases—with the option for AstraZeneca to select up to 40 drug products for clinical development.

“I am very hopeful and optimistic that modified-mRNA therapeutics will positively impact the lives of patients suffering from a wide spectrum of protein-deficiencies,” Rossi says.

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