NEW STRATEGY DRAMATICALLY IMPROVES GENE SILENCING WITH RNAi
Results published online today in Nature Structural & Molecular Biology
April 24, 2005
WORCESTER, Mass.- The ability to silence genes by RNA interference (RNAi) is emerging as one of the most important advances in biomedical research in recent decades. As potent as the technology of RNAi has proven to be, however, one of the conundrums in the field is that some genes haven't been amenable to substantial silencing when hit with the tools of RNAi . Now, a research team at the University of Massachusetts Medical School (UMMS) has made significant progress in solving this problem by developing an approach that has silenced some of those hard-to-knock-down genes; this effort could have important implications for the eventual development of therapeutics based on RNAi-induced gene silencing.
"We are pleased that this concept seems to work in a dramatic way," said Tariq M. Rana, PhD, professor of biochemistry & molecular pharmacology, leader of the UMMS team that developed the new approach. "By improving the target accessibility of the messengers the genes make, we increased the silencing effect from just 2 percent to 65 percent in the targets we studied. That's enough to make a difference."
The results of Dr. Rana's experiments that demonstrate the new technique were published online April 24 by the journal Nature Structural & Molecular Biology. In simple terms, Rana's group made the genes in question more susceptible to silencing by making the messages they sent more readable by the RNAi machinery.
RNAi was discovered in 1998 by Craig C. Mello, PhD, the Blais University Chair in Molecular Medicine, a UMMS professor of molecular medicine and cell biology and a Howard Hughes Medical Institute Investigator, in collaboration with his colleague Andrew Fire, PhD, then of the Carnegie Institution (now of Stanford University). The tools of RNAi give scientists a long-sought-after method for rapid and precise means to understand what genes do in the body and to interrupt the way genes direct the creation of proteins that regulate biologic functions.
To create proteins, genes send messages in the form of mRNA molecules to the protein producing factories within cells. RNAi uses a message-matching process to stop those mRNA molecules from reaching their destinations. To do that, RNAi tools contain a template with bits of information that correspond, one-for-one, with the information encoded on the messages sent by the genes. When the messages match up, the RNAi machinery destroys the messenger, thereby preventing protein production.
Some of those messages are quite easy to read, like a memo typed on a flat piece of paper. Others, however, are harder to see, as if the memo were folded and placed in an opaque envelope before being sent. Rana theorized that the genes which heretofore had been hard to silence were sending their messages in forms that were hard to read. To test that theory, his lab developed a way for the RNAi tools to grab hold of and rip open those opaque envelopes, then read the message inside. Once opened, if the message matched the one the RNAi tool was trying to silence, then the message was destroyed. "We had hypothesized that the accessibility of the target played a role in the efficiency of RNAi, whereas before the general assumption in the field was that it didn't matter," Rana said. "The value of this strategy is that we can be very specific in directing the RNAi machinery, even at these hard-to-target messengers."
Beyond their growing importance as research tools for identifying gene functions, the techniques of RNAi are emerging as a potential new class of therapeutic drugs because they could theoretically block the effects of disease-causing genes. RNAi compositions are now being aimed at many conditions including cancer, diabetes, Alzheimer's, Parkinson's and amyotrophic lateral sclerosis (ALS) as well as infectious diseases like HIV/AIDS and hepatitis. In that effort, silencing specific hard to silence genes may be vital. "We are gratified with these results, but our over-arching hope is that this will help spur additional research to enhance our understanding of this pathway, and prove efficacious for the translational efforts aimed at curing human disease," Rana said.
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The University of Massachusetts Medical School, one of the fastest growing academic health centers in the country, has built a reputation as a world-class research institution, consistently producing noteworthy advances in clinical and basic research. The Medical School attracts more than $167 million in research funding annually, 80 percent of which comes from federal funding sources. UMMS is the academic partner of UMass Memorial Health Care, the largest health care provider in Central Massachusetts. For more information visit www.umassmed.edu
Contact: Michael Cohen