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UMMS RNA Therapeutics Institute Aims to Bring Researchers Together, While Looking to RNAi and Beyond

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By Doug Macron

Creating an environment that brings together researchers working in basic science and those with a more clinical focus will be a key goal for the University of Massachusetts Medical School's proposed RNA Therapeutics Institute, according to its four co-directors.

"We have incredible strength at UMass in the basic sciences, generally, and in RNA and RNAi, specifically," UMMS investigator and RTI co-director Phil Zamore told RNAi News last week. "What we'd like to do is use that strength as a way of building a really complete research program that spans basic science all the way to clinical activities."

Citing a collaboration he has established with UMMS' Neil Aronin to develop siRNA-based treatments for Huntington's disease, Zamore noted that these kinds of relationships have so far resulted from "chance meetings." Going forward, "what we'd like to do is put people whose primary focus is basic science … in the same space as the people whose primary goal is to develop therapies for unmet human needs," he said.

At the same time, the RTI aims to foster research that will not only lead to the development of RNA-based drugs, such as RNAi molecules, but also small molecules and other agents that target RNA-related pathways.

For example, UMMS professor and RTI co-director Melissa Moore recently published a paper in the Journal of Biological Chemistry describing the use of a small-molecule inhibitor of pre-mRNA splicing as a potential cancer treatment.

"It's not using RNA as a therapeutic, but it is directing potential therapeutics at a process that involves RNA," and would be the kind of effort undertaken at the RTI, she told RNAi News.

UMMS began conceiving the RTI in 2007 after Massachusetts Gov. Deval Patrick proposed spending $1 billion over 10 years to grow the state’s life sciences sector (see RNAi News, 8/9/2007).

About a year later, the Life Sciences Act was signed into law, and UMMS received a $90 million funding commitment to support the construction of the Advanced Therapeutics Cluster to house an RNAi research center, as well as centers for gene therapy, stem-cell biology, and regenerative medicine, on its Worcester campus (see RNAi News, 6/26/2008).

Earlier this year, UMMS announced that it had decided to appoint four co-directors to the institute, while broadening its scope beyond RNAi to include all RNA-directed research (see RNAi News, 7/23/2009).

The RTI is not slated to officially open until 2012, but its co-directors, which also include Nobel Prize laureate Craig Mello and microRNA pioneer Victor Ambros, have begun meeting to lay the groundwork for how the institute is to be structured and the kinds of faculty that will be hired to fill out its roster.

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To Zamore, an important aspect of the RTI will be how it will form a nucleus of basic and clinically focused science.

"There is such a huge difference between having a collaboration with someone at another institution, or reading papers and trying to apply what they've discovered to your own work, and actually having that basic science colleague and the person with the intense clinical focus physically next to each other," he said. "You need to bump into people, to share the same equipment as other people … in order to have the conversations that really lead to the transfer of ideas out of the basic research lab to the technological side."

Zamore pointed out that having researchers with different goals working side by side often results in the adaptation of a technology for multiple purposes.

"Technologists often build tools for one purpose that turn out to be fantastic for other purposes," he explained. For example, "the very first efforts to implement large-scale RNAi screens were designed to make genetics in model organisms easier. But I'm sure that the largest … [of such] screens now are being done in secret in large pharma.

"They're not asking, 'What is the coolest gene in nematodes?'" he noted. "They're asking, 'What is the next drug target we should work on?'"

Echoing Zamore, Moore noted that the co-directors hope the new institute "will take advantage of physical proximity to come up with new and creative ways of working with things.

"I'm particularly interested in making sure we have enough interaction with the clinicians," she said. "A lot of times, clinicians interested in particular diseases don't even realize RNA could be a component of that disease."

And while the proximity of investigators within the RTI is expected to help accelerate research, Mello said that he envisions the institute also acting as a "hub … that draws on the expertise of [UMMS'] clinical system, as well as the school and every department.

Further, "we're looking for something that may even extend to … other institutions around here and in Boston and … bring together scientists on the campus and from outside," he said.

"The idea is to try to develop a new community that involves new faculty working in areas that bridge the basic science of RNA, gene expression, and cell biology to new kinds of approaches to treating disease," Ambros added.

Not Just RNAi

When UMMS disclosed that it had decided to expand the RTI's scope beyond just RNAi, the school's dean Terry Flotte said that the move reflected the co-directors' "varied interests and desire to define [the center's] mission around all therapeutics related to RNA biology."

Ambros pointed out that the original notion of an RNAi center in part stemmed from an effort to highlight the "themes that are inspired by Craig Mello's Nobel Prize" for his discovery of RNAi with Stanford University's Andrew Fire. "That evolved … somewhat to encompass all things RNA."

At the same time, there was the "realization that there is quite a diversity of pathways and complexes and phenomena that involve small RNAs [but] are not overtly RNAi as we think of it," he said. "There are all these phenomena that involve reactions in the nucleus, the substrates are nascent transcripts, and the DNA."

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Mello noted that the choice of RNA over just RNAi reflects the "recognition that RNA is an extremely important part of any disease.

"Certainly, RNAi is an important tool, but the concept of calling [the institute] an RNA therapeutics center … [makes] clear we're emphasizing the whole field of RNA biology that is so important in disease," he said.

Zamore agreed.

"I certainly wouldn't have any interest in setting up an institute with the sole focus of developing siRNAs for use in patients," he said. "You can have disease that is a gain of function and you can have a disease that is a loss of function; not all of those are amenable to turning genes on or off.

And with respect to RNAi, "off is not always the answer," he said. "There are other kinds of strategies that involve nucleic acids like switching splice sites, using RNA to stimulate the immune system, and then there is the raft of applications of nucleic acids that are still a couple of steps back from the clinic."

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