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RNAi Roundup: Technology Reveals Molecular Secrets of Aging; Sirna, Now Financially Stable, Touts Stability of Chemistry; Qiagen Reports Growth in siRNA Business

NEW YORK, May 16 -- RNAi just may be the string that pulls back the curtain on the secrets of aging and reveals a molecular fountain of youth: A team of modern-day Ponce de Leons at the University of California, San Francisco, report in this week's Science using the technology to identify transcription factors in C. elegans that, when stimulated, increase lifespan and stop aging.


"We think we've found an important physiological explanation for both aging and age-related disease," said head researcher Cynthia Kenyon, in a statement. "The question of why older people are more susceptible to so many diseases has been a fundamental, unsolved problem in biology. Our findings suggest a beautiful molecular explanation, at least for this protein-aggregation disease."


Kenyon, along with first author Ao-Lin Hsu and Colleen Murphy, used RNAi to knock out the gene HSF-1 and found that the aging of tissue was accelerated and the organism had a shortened lifespan. Further RNAi experiments on this gene in combination with another transcription factor, DAF-16, showed that these two appear to work together.  Finally, overexpression of these genes also led to increased lifespan and delayed tissue aging in C. elegans.


The group wrote that overexpression of these genes leads to an increase in certain heat shock proteins, which delay the aggregation of polyglutamine-expansion proteins.


"By preventing damaged and unfolded proteins from aggregating, this one set of proteins may be able to stave off both aging and age-related disease," Kenyon explained. "The small heat-shock proteins are the molecular link between the two."


In addition to unlocking aging secrets, RNAi also appeared to be showing promise in the therapeutic arena this week. A group of researchers, led by Anton McCaffrey of Mark Kay's Stanford lab, reported this week in Nature Biotechnology online on their use of RNAi to inhibit hepatitis B virus in mice.


McCaffrey, who pioneered an effective vector for RNAi inhibition in in vivo mouse models, (Nature 2002 Jul 4;418(6893):38-9.), described in a May 12 Nature Biotechnology article how RNAi inhibits HBV replication in cell culture and in mice. The group transfected the mice with HBV plasmids, then with plasmids that expressed short hairpin RNAs that were homologous to mRNAs produced by HBV. Examination of the liver revealed that levels of HBV were "substantially reduced," the researchers reported. Serum and cell culture analysis also showed a substantial reduction in activity.


Other RNAi papers of note this week included one that used DNA microarrays to validate the specificity of short interfering RNA in knocking down genes, published in Proceedings of the National Academy of Sciences online May 13; one on endogenous siRNAs in C.elegans (Curr Biol 2003 May 13;13(10):807-18); one using RNAi to explore the effects of a deficiency in Centrin, a calcium-binding protein, in Chlamydomonas (J Cell Sci 2003 May 13; published online); and a paper in which RNAi was used to inhibit tbCPSF30 protein in Trypanosoma brucei (J Biol Chem 2003 May 13; published online).


In the commercial arena, Sirna Therapeutics reported a reduction in first-quarter revenues Wednesday, amid reduced losses and expenses.


The company, a former antisense therapeutics firm that remade itself into an siRNA therapeutics company last month after raising $48 million in a round of financing, reported revenues of $.5 million for the quarter, down from $1.6 million from the year-ago quarter. R&D expenses, meanwhile, decreased to $3.8 million, from $6.7 million in the first quarter of 2002.


The company lost $5.5 million for the quarter, compared to $8.5 million in the first quarter of 2002. At the end of March, the company, which formerly carried the name Ribozyme Pharmaceuticals, had $4.9 million in cash, compared to $8.9 million at the end of December. In other words, at the current burn rate, the company would have run out of cash some time in July, had it failed to raise additional funds.


Now that Sirna has been given a new lease on life, company scientists have been touting the advantages of its experience with RNA chemistry. At the recent RNAi meeting in Waltham, Mass. earlier this month, David Morrissey, associate director of biology at the company, discussed the company's development of siRNA-like molecules that lack the ribose sugar. Through experience with antisense, Morrissey said, the company has learned that the ribose sugar makes the interfering molecule unstable. So they have designed a molecule with a "ribose prosthetic" to hold it together. These "siNAs" display much higher long-term stability in silencing genes than the ones containing ribose. Morrissey showed data from a study of gene silencing involving hepatitis B, where the siRNA molecule was more active at day 3, but the modified no-ribose molecule was much more active at day 21. This stabilized molecule also showed a lack of toxicity. Of course, as with nearly all studies of siRNA or similar therapeutics, this stabilized molecule has not been validated as a knockout of gene functions in humans.


Also at the meeting  (reported on extensively in last week's RNAi Roundup), Eric Lader, who recently joined Qiagen as its global business manager for the gene silencing group from Ambion, presented on the company's methods for making and validating siRNA. The company validates its siRNA with high-throughput RT-PCR, which is becoming standard. Unlike its rival Dharmacon, Qiagen limits its sequence selection guidelines to the standard group of rules developed by siRNA co-inventor Tom Tuschl. 


When it comes to the future of RNAi, Lader is unabashedly bullish. "Advances in design, delivery, and analysis mean that the promise of RNAi as a tool and possibly a therapeutic may be realized faster than anyone anticipated," he said in a recent e-mail to GenomeWeb.


Perhaps this outlook comes from the numbers Qiagen reported earlier this month in its quarterly results announcement. Overall, the company's revenues and net income were up. But CEO Metin Colpan reported that the company's synthetic nucleic acid business grew 24 percent during the quarter, and that this growth "was driven by an increasing demand of newly introduced gene sets and siRNA."  Seeking to build on this momentum, Qiagen has launched a new gene silencing product "4-for-Silencing," and is planning to hold an siRNA workshop at the Oligonucleotide Technologies conference in Cologne, Germany, next week.


In the innovation arena, the combination of RNAi and microarrays is the latest bleeding-edge laboratory technology. Spyro Mousses, who recently joined the Translational Genomics Research Institute from NHGRI, and Vivek Mittal, of Cold Spring Harbor Laboratory, have both been using microarrays with RNAi probes to knock out gene function in cells using the reverse transfection cell microarray method pioneered by Whitehead fellow David Sabatini. CombiMatrix, of Squolamie, Wash., has meanwhile been using its semiconductor microarrays as RNAi synthesis factories, according to CEO Amit Kumar. For more details, see this week's BioArray News.

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