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Benitec Licenses Calando Delivery Technology For Hep C as It Looks Beyond Expressed RNAi


Arrowhead Research subsidiary Calando Pharmaceuticals has exclusively licensed the rights to use its proprietary polymeric nucleic acid delivery technology to Benitec for use in the development of an RNAi-based hepatitis C therapy, the parent company said this week.

Under the terms of the deal, Calando will receive an upfront payment, as well as milestones and royalties from a commercialized product. Additional terms were not disclosed.

The deal marks the most tangible evidence of the company's decision to look beyond expressed RNAi to the possibilities of delivered RNAi.

Benitec was founded to develop and commercialize its so-called DNA-delivered RNAi technology, which involves the knocking down of gene expression using DNA that transcribes double-stranded RNA, one strand of which has a sequence complementary to that of the target gene.

However, when Benitec announced in April that it had struck a cross-licensing deal for intellectual property with Alnylam Pharmaceuticals, CEO Sara Cunningham indicated to RNAi News that her firm had begun to consider other RNAi technologies, including delivered RNAi (see RNAi News, 4/15/2005).

In line with this, Benitec has licensed Calando's delivery technology with the intention of seeing whether it can be used with the company's hepatitis C clinical candidate, which consists of "three highly functional sequences … against three regions of HCV … that all exhibit 85 percent or greater inhibition," Cunningham told RNAi News this week.

"If you express plasmid DNA in mice, you'll see loss of expression fairly quickly." While people had assumed the DNA was degraded, it was actually still there. In fact, "it was just that the transcription had been shut off."

According to Calando, its delivery technology comprises a linear, cyclodextrin-containing polycation that is able to bind to the anionic backbone of an siRNA. When mixed together, the polymer and siRNA self-assemble into nanoparticles, roughly 50 nanometers in diameter, which are protected from nuclease degradation in blood serum.

The cyclodextrin in the polymer, Calando said, allows stabilizing agents to be attached to the surface of the particles. These agents have terminal adamantane groups that form inclusion complexes with cyclodextrin and contain polyethylene glycol, which prevents aggregation while preventing degradation. Additionally, ligands to cell-surface receptors can be covalently attached to the adamantane-PEG modifier, Calando notes, which allows the particles to be targeted to tissues of interest.

According to Cunningham, data from Calando showing the technology could be used to deliver siRNAs targeting luciferase-expressing human Ewing's sarcoma cells in a mouse model proves the approach is effective for delivered RNAi. As such, Benitec plans to use it to deliver a therapeutic that will consist of pooled siRNAs expressing the three hepatitis C sequences the company is targeting.

Additionally, she said, Benitec is collaborating with the labs of Stanford University School of Medicine researcher Mark Kay and California Institute of Technology scientist Mark Davis to see if Calando's technology can also be used to deliver shRNA-expressing mini-circles that express the sequences. (Kay founded Avocel, which Benitec acquired about a year ago [see RNAi News, 5/21/2004]). Davis co-founded Calando with City of Hope's John Rossi, a scientific advisor to Benitec.)

Describing the mini-circles, Cunningham noted that "if you express plasmid DNA in mice, you'll see loss of expression fairly quickly." While people had assumed the DNA was degraded, "Mark Kay … found the DNA was [still] there, it was just that the transcription had been shut off," she said.

Kay and his colleagues "started tinkering with a plasmid backbone, and finally found that if you take out all of the bacterial genes so that there're no bacterial sequences covalently linked to the plasmid DNA, then you can get expression from these plasmids for the life of the mouse," Cunningham explained. "These are the mini-circles, [which] can be used to express multiple shRNA."

Cunningham said that the mini-circle and pooled siRNA drug candidates, which will be delivered with Calando's technology, will be compared with a hepatitis C therapy being developed with Benitec's own ddRNAi technology, which is delivered with a viral vector. The most effective will be advanced into the clinic.

No matter which version of the hepatitis C drug candidate Benitec ends up testing in humans, Cunningham noted that the company remains certain that a multi-target approach will be necessary to develop an effective hepatitis C therapy.

"With one siRNA, [the virus] will generate escape mutants just like it does against small molecule drugs, so you really do have to hit multiple sequences simultaneously," she said. "So whether we entrap [with Calando's delivery technology] multiple shRNA or mini-circles that encode for our clinical candidate, which is three sequences against three regions of HCV, we feel very comfortable that we will be able to block viral replication of HCV across multiple genotypes."

Cunningham noted that Benitec still envisions meeting its previously disclosed timeline of entering a hepatitis C drug candidate into phase I testing by the end of 2006. She added that the company plans to begin testing the efficacy of a ddRNAi-based drug candidate, delivered using adeno-associated virus vectors, in marmosets around the end of July.

"Regardless of the delivery mechanism, the mode of action is the same," she said. "So we'd like to see as quickly as possible in an animal model [whether] we can block replication of HCV. By the end of the summer, we'll have those data," Cunningham said.

— Doug Macron ([email protected])

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