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Silence Takes Aim at mRNA Therapeutics as RNAi Cancer Drug Advances

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NEW YORK (GenomeWeb) – Amid a growing interest into the therapeutic potential of messenger RNA, Silence Therapeutics has released preclinical data showing that its liposomal delivery vehicles can be modified to carry mRNA payloads into a variety of organs and can trigger expression of a human protein in the bloodstream.

According to Silence CEO Ali Mortazavi, the work stems from ongoing efforts to "redesign Silence from a technology company into … a full-functioning biotech." So while the company's lead molecule remains the siRNA-based cancer drug Atu027, Silence may choose to move forward with an mRNA replacement therapy as its next clinical candidate depending on the outcome of planned non-human primate testing, he told GenomeWeb.

Silence has long focused on Atu027, a blunt-ended siRNA targeting the protein kinase PKN-3 that is delivered systemically using the company's vascular endothelium-targeting lipids, and recently completed enrollment in a Phase IIa study of the drug in combination with the chemotherapeutic gemcitabine in pancreatic cancer patients. A Phase I trial in head and neck squamous cell carcinoma is planned for early 2015.

Yet in the more than 15 years since Silence — originally known as Atugen — was established, Atu027 remains the only compound the firm has brought into human testing. At the same time, the company has experienced a number of management changes, at one point seeing the departure of three of its top executives in just two years.

With Mortazavi now at the helm, Silence is aiming to be more than just an RNAi drug developer with a single clinical candidate by exploring other therapeutic modalities for use with its core delivery technologies. "We want to choose the best idea [and] get away from choosing the only idea," he said.

To that end, Silence has started working in the burgeoning field of mRNA-based therapeutics, which landed on many people's radar screens when AstraZeneca inked a $240 million partnership with mRNA startup Moderna Therapeutics in 2013. Since then, RNAi companies including Dicerna Pharmaceuticals, Tekmira Pharmaceuticals, and Arcturus Therapeutics have all publicly expressed interest in using their delivery technologies for mRNA drugs.

And now Silence has joined them. According to data provided to GenomeWeb, Silence has been able to adapt its liposomes to carry mRNAs into both the lungs and livers of mice, and has been exploring chemical modifications, as well as untranslated regions and codon optimization, to improve their protein expression and reduce related immune stimulation.

Further, using its liver-directed mRNAs, Silence said it has been able to trigger a 100,000-fold increase in circulating human erythropoietin in mice, establishing proof of concept for its mRNA delivery platform. Silence is now preparing to try to replicate these findings in non-human primates in a study planned for the first quarter of next year.

Should that effort prove positive, Mortazavi said that Silence might scuttle is its next siRNA drug candidate, the acute lung injury drug Atu111 in favor of a lung-targeting mRNA therapeutic.

Atu111 is designed to silence the vascular growth factor angiopoietin-2 and is delivered using a technology that targets pulmonary endothelial cells. But "we think we can do better than the current target of Ang2," Mortazavi said, and Silence may decide to swap out the drug's siRNA payload for a yet-to-be-determined mRNA one.

But while Silence is moving "headlong into mRNA therapeutics," he stressed that the field is still in its infancy, comparing it to the RNAi therapeutics space of a decade ago, and that Silence is still trying to understand the limitations and stress points of the technology.

As it does so, it will continue to move Atu027 forward, in large part because the drug has helped establish the safety of Silence's delivery technology in humans, while evaluating a variety of other potential RNAi targets.

"We're giving this [cancer] program a shot," and will continue advancing it should any signs of efficacy be observed in the clinic. At the same time, "we're trying to show our investors that they're in a biotech company that is not just about one product."

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