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Broad Institute in Final Stages of Putting Together RNAi Consortium

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RNAi-based screening may get a little bit easier if a new initiative by the Cambridge, Mass.-based Broad Institute is successful. The institute — a Harvard-MIT joint venture recently founded to develop and provide tools for “genomic medicine” — is in the final stages of establishing a public/private consortium of RNAi researchers focused on the development and public release of genome-scale sets of virally expressed shRNAs targeting mouse and human genes, RNAi News has learned.

According to David Root, project leader at the RNAi Consortium, the effort is an outgrowth of a nearly 2-year-old alliance between various researchers at the Whitehead Institute’s Center for Genome Research, the Dana Farber Cancer Institute, the Massachusetts Institute of Technology, and Harvard University.

“The consortium came about from a number of people at MIT and Harvard who were interested in being able to do screening with RNAi,” he told RNAi News.

In 2001, these researchers “got together in an informal effort to explore RNAi screening and making retroviruses, lentiviruses, to introduce shRNAs,” Root explained. “People were working on things themselves, in their own labs for their own purposes, [and] … a few of them got together and decided to coordinate their efforts on some level.”

The result was a loosely knit alliance of investigators working to put together shRNA libraries that could be made freely available to other academics working in the field. Among the most active members of the group, Root said, are Eric Lander, director of the Center for Genome Research; William Hahn, assistant professor at Dana Farber; Massachusetts General Hospital associate professor (and former Whitehead fellow) Nir Hacohen; Whitehead fellows Sheila Stewart and Brent Stockwell; and David Sabatini, MIT professor and associate member of the Whitehead Institute.

To date, the researchers have established a limited, but “considerable” set of shRNAs expressed using lentivirus and Moloney leukemia virus vectors, as well as a “rapid” production method that “permits scaling up to high levels,” Root said. “We can produce a fairly high rate now,” he noted, declining to go into detail.

The consortium’s goal is to create a genome-wide library of shRNAs that generate siRNAs within the cell from viral vectors. According to Sabatini’s MIT website, the library “will consist of bacterial glycerol stocks harboring sequence-verified shRNA Moloney and lentiviral vectors for mouse and human genes with four to five monoclonal stocks per gene.”

The shRNAs will be designed for use in tissue culture gene silencing experiments, but may have in vivo applications such as developing transgenic mice, Root said. The RNAi Consortium will also “continue to develop vectors and continue to work on new library designs as we build a large [shRNA] set,” he added.

Specific projects beyond the shRNA library that the RNAi Consortium will undertake have yet to be finalized but are being discussed with potential investors from the private sector, Root said.

He said that the Broad Institute is currently in negotiations with undisclosed companies about funding the RNAi Consortium; the approach it will take to meet its key goal of making the shRNA libraries public; and the emphasis that will be placed on other programs. He declined to comment on how much money is being sought for the consortium, but noted that additional details would likely be available in the next four to five weeks as the talks advance.

While it remains unclear how Broad’s RNAi Consortium will get its shRNA library into the hands of other researchers, it is possible it will follow the lead of two other academic groups, which decided that deals with Open Biosystems — a start up founded in 2002 for the purpose of making research tools available and affordable to academic customers — would be the way to make their shRNA and dsRNA libraries widely available.

In late March, Open Biosystems announced that it has begun selling the human and mouse shRNA libraries developed by the lab of Cold Spring Harbor Laboratory’s Greg Hannon. The shRNA clones in the libraries are expressed from DNA vectors and target over 6,500 genes with one to four shRNA clones per gene, according to Open Biosystems. The libraries are expected to be expanded to include all validated human and mouse genes, with six to 10 shRNAs per gene, the company added.

Troy Moore, chief technology officer at Open Biosystems, told RNAi News that the deal for the shRNA libraries came out of discussions with Hannon and former Cold Spring Harbor Lab researcher Doug Conklin. “I’ve talked with Doug ... and Greg over the years,” and “we ended up participating with them a lot” on the libraries’ development, he said.

John Maroney, Cold Spring Harbor Lab’s director of technology transfer, told RNAi News that Open Biosystems was found to be the best partner for the research institution — highly competent in the science of RNAi and with a genuine interest in making the libraries accessible, unlike some of the other potential collaborators considered.

Open Biosystems is also the marketer of a Drosophila RNAi library developed by researchers from the University of California, San Francisco. This library currently consists of dsDNAs covering half of the Drosophila genome, according to Open Biosystems.

Moore said that UCSF researcher Pat O’Farrell spearheaded the Drosophila RNAi effort and approached Open Biosystems last year about forging a distribution arrangement for the library, which was launched late last summer.

As for the Broad Institute’s RNAi Consortium, Moore said that “we’ve talked with them some … as they were doing some of their proof-of-concept work … [but] they’re still pretty early” in the development process.

Moore noted that his company does not have any sort of formal arrangement with the Broad Institute, but said that “we’d certainly be interested because no one’s got the absolute design of these things down yet so there’s certainly room to have a couple more collections.”

— DM

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