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RNAi Roundup: Ribozyme Becomes Sirna; Benitec Licenses IP to Promega; Pat Brown Shows Specificity of RNAi

NEW YORK, April 18 - In a sign that RNAi is truly creating a buzz in the life sciences community, Ribozyme Pharmaceuticals announced Wednesday that it was changing its name to Sirna Therapeutics, and changing its stock symbol to RNAI.

 

This move is similar to corporate makeovers in the heyday of the genomics boom, such as Incyte Pharmaceuticals' name change to Incyte Genomics. (The company is now just "Incyte".) Just as Incyte and others wanted to reflect the centrality of the genome to their research in their company name, this change reflects Sirna's new emphasis towards RNAi and away from ribozyme-based therapeutics.

 

"We've really shifted the focus of the company from ribozymes to the mechanism of RNAi, because we really believe ...that we are the leaders in this field," said Howard Rogin, president and CEO of the company. "I am sure we are well ahead of everyone else working in RNA interference," he added.

 

The company is jumping whole hog into RNAi because of the results that RNAi produces, according to Robin.

"We saw fairly decent results with ribozymes," he said, "but when we do our work with siRNA, we see perhaps 200 times more potency. That's the beauty of RNAi - because it's part of the natural cellular machinery, you can do with a few constructions of siRNAs what has taken hundreds of ribozymes to do."

 

One ribozyme-based project with Chiron on a therapeutic for metastatic colon cancer will continue, but all future research at Sirna will revolve around RNAi.

 

The company made this change just after raising $48 million in a private round of venture capital led by the Sprout Group.

 

The company aims to distinguish itself from the RNAi pack through the 50 patents it has on RNA and 30 patents on chemical modifications for stabilization of RNAi. The company's inventions include siNAs - short interfering nucleic acids. Robin said these siNAs and its siRNAs are "extremely stable," and that the company plans to publish efficacy data soon on the use of these nucleic acids in hepatitis B, hepatitis C, and macular degeneration.

 

The intellectual property concerns over RNAi, however, promise to produce a typhoon of litigation in the near future.

 

Few patents have as yet issued on RNAi but this has not stopped licensing activity. MIT is widely believed to have cornerstone patent applications in short interfering RNAi, which it has licensed exclusively to a single company, Alnylam, in the therapeutic arena, and co-exclusively to four companies for target validation - Ambion, Proligo, Dharmacon, and Qiagen.

 

But Sirna Therapeutics does not see its lack of a license from MIT as a problem- at least not yet. "We looked at this IP and other IP, and it's certainly interesting but no one knows how it will shake out," said Robin.

 

While he did not rule out the idea of paying royalty fees in the case that a patent is issued, Robin pointed out the company's patents on chemical modifications for stabilization of RNAi. "If you don't have the chemical modifications, you can't turn [RNAi] into therapeutics," he said.


 

In another intellectual property development, Benitec, of St. Lucia, Australia, announced last week that it had exclusively licensed its RNAi-related inventions to Promega. Benitec has invented DNA-delivered RNAi, an alternative to siRNA, and has applied for patents worldwide on this method.

 

Like siRNA, DNA-delivered RNAi, or ddRNAi, selectively silences genes by triggering the cell to destroy mRNA. This inhibition of the mRNA happens when a double-stranded stretch of RNA, dsRNA, is introduced into the cell, with one strand being identical to that of the mRNA targeted for destruction.

 

According to Benitec, ddRNAi involves introducing DNA constructs that produce the dsRNA within the cell, whereas siRNA involves directly introducing the dsRNA into the cell. Benitec uses inverted repeat DNA constructs, which are then transcribed to produce the RNAi transcript within the cell. This transcript forms a double-stranded hairpin, and then is cleaved by RNase, and then direct recognition of homologous mRNA, targeting them for destruction by a protein complex.

 

Under the agreement, Benitec will receive a license fee and future royalties after its worldwide patents issue.

 


Meanwhile, on the research front, Jen-Tsan Chi and colleagues from microarray pioneer Patrick Brown's lab at Stanford published a paper, "Genome-wide view of gene silencing by small interfering RNAs," online in the Proceedings of the National Academy of Science. In the paper, the group tested whether siRNA gene silencing in human cells has unintended effects of silencing genes that are 5' to the initial target sequence - a  phenomenon known as "transitive RNAi" - and whether siRNA gene silencing causes global changes in gene expression - a result that would indicate that siRNA has unintended effects on cellular mechanics.

 

The group transfected human kidney cells with green fluorescent protein reporter genes, and then targeted the siRNAs toward these genes. Comparing these RNAi cells to control cells and mock treatment cells, they found no significant differences in global gene expression.

 

They also looked for the transitive RNAi by co-transfecting two reporter genes, GFP/YFP, and luciferase, into the cells side by side, and then directing the siRNAs at the GFP/YFP genes. While the siRNA did silence the GFP/YFP genes, it did not block the luciferase activity.

 

"By using DNA microarrays to profile global gene expression, we have demonstrated that siRNA-mediated gene silencing has exquisite sequence specificity for the target mRNA and does not induce detectable secondary changes in the global gene expression pattern," Chi and colleagues wrote. "Although it will be important to examine the possibility that different mammalian cell types might respond to siRNAs differently, these results provide further impetus for using siRNA-mediated RNAi as a research and therapeutic tool."

 

Other research papers published this week in the RNAi area include one in Nucleic Acids Research by a group at Novartis, on combining antisense and RNAi to inhibit the recombinant Rat P2X(3) receptor, a pain-related cation channel; a paper in Experimental Cell Research on using siRNA to suppress expression of epidermal growth factor receptors in human epidermoid carcinoma cells; a paper in Biochemistry & Biophysical Research Communications on use of RNAi in murine models to knock down vascular endothelial growth factor in cancer; and two papers that used RNAi to study sensory organ function in Drosophila, and RNA capping in C. elegans.

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