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Silencing Doubts

No one has yet tried RNAi in humans, but one company is close: Ribopharma, a biotech startup in Kulmbach, Germany. More than a year before Tuschl’s group stunned the scientific community with its news, Ribopharma’s founders, former Bayreuth University lecturers Roland Kreutzer and Stefan Limmer, discovered that small RNAs worked in mammalian cells. Or so Kreutzer and Limmer claim. They have never published their data.

Kreutzer and Limmer reasoned that it was physically impossible for the very long RNAs, such as those used by Fire and Mello, to bind all at once to their target RNAs. Only short segments would stick. So they tried silencing mammalian genes using RNAs short enough to evade the fatal immune response. “It wasgambling,” says Limmer. “And it turned out that it really works.” The researchers filed a patent application, quit their teaching jobs, and in June 2000 founded Ribopharma.

Ribopharma’s principals are planning to begin human trials next year, probably starting with tests of small interfering RNAs in the treatment of malignant melanoma and pancreatic cancer. Kreutzer and Limmer say their RNA constructs are stable enough to work without vectors and can be injected directly into the site of a tumor or into the bloodstream. The company has raised more than $18 million. But because Ribopharma has yet to publish its results, it’s difficult to evaluate its claims, say other RNA researchers. “They’ve been doing some things,” says MIT’s Sharp, “quite nicely….[But] it’s a long road.”

How long? Attitudes range from Ribopharma’s sanguine assurances to strong pessimism. David Beach, president of RNAi startup Genetica in Cambridge, MA, points to antisense’s decade-plus odyssey. “I don’t want to sit and argue deploying RNAi in a therapeutic mode would be any simpler,” he says.

What is far clearer is that RNAi is forcing biologists to rethink RNA’s role. In the last few years, researchers have found hundreds of genes that code for small RNA molecules, dubbed “microRNAs,” in organisms ranging from plants and worms to humans. Like their small interfering RNA cousins, microRNAs appear to silence genes, but their role in biology is mostly unknown. “Many of them have been very highly conserved during the course of evolution; [so] they must be doing something important,” says MIT biologist David Bartel. Meanwhile, the realization that RNAi is a natural-and probably fundamental-process in plants and animals has helped make it one of the most exciting mysteries in today’s biology.

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Tagged: Biomedicine

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