Can drugs that supposedly “activate” a controversial target—sirtuin proteins—stop or even reverse the aging process? A new report this week said “No.” According to this report, published Wednesday night in Nature, sirtuin activators do not extend lifespan in roundworms and flies and earlier studies that said they did were flawed. Nonetheless, GlaxoSmithKline (GSK) continues to invest hundreds of millions of dollars into developing drugs to hit these targets—more about their findings below—and if the drugs work, for whatever reason, the scientific squabbles will not matter.

I recently had the chance to hear Harvard professor David Sinclair talk publicly about his and GSK’s research into sirtuin activators. Sinclair was the scientific founder of Sirtris and he reported at a forum on longevity in Cambridge, MA, that GSK has high hopes of near-term confirmation in mice that some sirtuin activators do extend lifespan. Based on its continued investment, GSK still believes that the $720 million acquisition of Sirtris in 2008 was a smart one.

The Nature report, just the latest in a series of publications that question the sirtuin-longevity link, will be even tougher for Sinclair and other sirtuin researchers to overcome. The new research reported that sirtuin proteins, when overexpressed in nematode worms and fruit flies, do not actually have an effect on longevity. This directly contradicts the original publications linking Sir2 and other sirtuins with increased lifespan. The new report further goes on to contradict the landmark 2006 paper, also published in Nature, in which Harvard researchers led by Sinclair reported that mice fed resveratrol which, they demonstrated using expression analysis, activated sirtuins, live on average 20 percent longer and in some cases much longer than that.

The same researchers, both at University College London, went on the record as sirtuin skeptics in 2007. David Gems and Linda Partridge then set out to prove their claim that the original sirtuin and resveratrol findings, which led to the founding and eventual acquisition of Sirtris, were irreparably flawed. Building on earlier reports that the round worms used in the original studies carried a gene that control organisms did not carry, and that it was this gene that predisposed the worms to live longer, Gems and Partridge showed in this paper that organisms identical to one another except for the expression level of sirtuins could not be made to live longer.

Sirtuin research is nothing if not contentious. Apparently eager to fan the flames, Nature in the same issue this week published a rebuttal from Leonard Guarente, the author … Next Page »

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Research into the use of RNA interference (RNAi) to “silence” gene activity is picking up steam (see our story two weeks ago about Alnylam’s RNAi-based treatment for RSV), but it’s still very difficult just to get RNAi agents inside cells, where they can actually do their jobs. Today Waltham, MA-based Thermo Fisher Scientific unveiled a new agent that it says can be absorbed by cultured cells directly “without the use of conventional delivery methods such as transfection reagents, viruses or electroporation.” Such an agent could significantly speed any biomedical or pharmaceutical research project in which RNAi is used to shut off specific genes, according to Thermo.

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Boston-based RNAi therapeutics startup Dicerna is finally officially out of the gates with a finalized $13M Series A financing led by Oxford Bioscience Partners and Skyline Ventures. (I profiled Dicerna last week.) Co-founder Doug Fambrough of Oxford Bioscience Partners is Chairman and Skyline Ventures’ Stephen Hoffman is also joining the board. Dicerna’s CEO is James C. Jenson, and SVP of Pharmaceutical Development is Roberto Guerciolini, both of whom are also co-founders. Dicerna’s core “Dicer substrate technology” was discovered by co-founders John Rossi, of City of Hope’s Beckman Research Institute, and Mark Behlke, at Integrated DNA Technologies. The company claims its novel approach to RNAi opens up new avenues for drug discovery and development previously shut off by other companies’ intellectual property claims.

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If all goes as planned, Cambridge-based RNAi pioneer Alnylam (NASDAQ: ALNY) will be celebrating Thanksgiving with a new competitor in its backyard, in the form of Dicerna Pharmaceuticals, a brand-new startup fueled by about $13 million from Oxford Biosciences. Dicerna capitalizes on a new approach to making gene-silencing medicines that sprang from the laboratory of a co-founder, John Rossi, at City of Hope in Duarte, CA.

If Rossi gets his wish, even more little RNAi companies will soon follow.

“There’s always a need for more companies, so you can treat more diseases,” Rossi says. But before, “Nobody else could make [RNAi-based drugs] unless you wanted to get a license from Alnylam.”

Though some people argue that Alnylam has oversold its position, many observers agree with Rossi that the Cambridge firm’s patent portfolio gives it a big competitive advantage in the RNAi therapeutics arena. But because Dicerna is built around a new approach to RNAi, Rossi says, “we’ve just formed a company whose choices are wide open.” Dicerna hasn’t yet selected which diseases it will target, and its IP is still at the application stage, but according to Rossi the company will provide licenses to others as well as developing its own therapeutics.

It’s not too surprising that Rossi is the catalyst of this new endeavor. Though he keeps a lower profile than some of RNAi’s other big names, he is one of the most widely respected and prolific pioneers of research into applying the technique—in which short strands of RNA are used to turn genes off—to treat diseases. His lab is working at the field’s cutting edge, doing some of the earliest human trials (in HIV patients). That work involves tinkering with the molecules themselves: Changing their chemical makeup even slightly can make them more powerful or less likely to cause side effects.

It was through such tinkering that Rossi made a surprising discovery.

Previously, like most other experts, Rossi believed that the specific length of Alnylam’s RNAs was ideal for gene silencing. But while trying to get better results in his experiments, “We noticed that if [the strands] were a bit longer we got more potent knockdown,” Rossi says. It was good news that the longer strands actually worked. The fact that they seem to work better than the short ones is even more exciting—more powerful knockdown should mean that less drug is needed.

Dicerna cofounder Mark Behlke, a vice president at Coralville, IA-based biotech supplier Integrated DNA Technologies (IDT), heard Rossi give a talk about this approach and the two soon became collaborators. They ended up developing these new “dicer substrate siRNAs” jointly. Dicer is the natural cellular machinery that chops these longer RNA strands up and turns them into silencing tools. City of Hope and IDT own the patents on the technology, which Dicerna has now licensed.

With two of its founders out of state, how did Dicerna wind up in Boston? For one thing, the company’s VC backers, its CEO, and a third co-founder—Doug Fambrough, a partner at Oxford who will be chairman of the board—are here. What’s more, says Rossi, “Boston is a rich environment for drawing upon highly trained personnel and provides a rich intellectual environment for employees, such as seminars, collaborations and other business related activities.”

Dicerna is scheduled to be formally launched in November. That news broke ahead of when the startup wished it would on the In Vivo blog last week. “The financing has not been finalized, but we’re anticipating $13 million, and we’re not looking for additional financing at this time,” says Fambrough. [11-14-07 Update: Dicerna announced today it has closed the financing and that Skyline Ventures is co-lead investor with Oxford Bioscience Partners on the $13 million deal. ]

Rossi feels efforts at commercializing RNAi have lagged recently. (The first drug based on the technology has yet to be approved). He says that since Merck gobbled up Alnylam rival Sirna, “We don’t know what is going on there.” Another player, CytRx, recently spun out its RNAi therapeutics program into a new subsidiary called RXi, but has not yet announced any product candidates. “Alnylam is really the only company doing very much right now,” he says.

Rossi is heartened that more new companies are forming, however. “I’ve heard of a couple, but they are not public yet,” he says. With Dicerna now adding to the IP mix, things could get even more interesting.

Though he points to challenges ahead, such as choosing the right disease targets and overcoming the drug-delivery hurdles facing all RNAi efforts, Rossi is confident that things will indeed get interesting. “These drugs are going to move faster than others,” Rossi says. “The discovery [of RNAi] was only made 9 years ago, and now there are already clinical trials. How long did it take to get the first monoclonal antibodies that far?”

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