c&en | For small biotech companies hoping to strike a deal with larger drug developers, there’s no greater destination than the J.P. Morgan Healthcare Conference. In early January 2020, leaders from the start-up Shape Therapeutics made the annual pilgrimage to this mecca of biotechnology networking in San Francisco to make a pitch: What if you could edit someone’s genetic code without ever touching their DNA?
The biotech industry is awash in companies using tools like CRISPR gene editing to fix or turn off problematic DNA. If gene editing works, it could provide a one-and-done cure. But some researchers are worried that if CRISPR slips up and cuts DNA at the wrong site, the damage could also be permanent. “Targeting DNA has a lot of all-or-nothing consequences,” says David Huss, head of research at Shape.
At the conference, Huss explained to potential partners that Shape’s solution was to edit RNA instead of DNA. Our cells constantly produce short-lived RNA molecules that convert the DNA code into functional proteins. Incredibly, our bodies have already evolved an ingenious tool for editing RNA: an enzyme called ADAR—adenosine deaminase acting on RNA. The enzyme converts select adenosine (A) bases, one of four letters that compose the messenger RNA (mRNA) code, into another base that the cell interprets as guanosine (G). Shape was founded in 2018 on the basis of academic work showing that synthetic molecules called guide RNAs could recruit ADAR and direct it to make these A-to-G edits at precise sites.
Scientists estimate that A-to-G editing could fix mutations responsible for nearly 50% of genetic diseases. “We have a tool that can be applied to so many diseases that we couldn’t possibly do them all ourselves,” Huss says. When Shape executives pitched their RNA-editing technology to the Big Pharma company Roche, the two teams clicked, says Sylke Poehling, head of therapeutic modalities at Roche.
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