Gene silencing takes steps forward

Dicerna Pharmaceuticals and Ipsen to collaborate on therapeutic agents in endocrinology and oncology

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WATERTOWN, Mass.—In announcing a new collaboration with Ipsen in Paris, Dicerna Pharmaceuticals seems poised to move forward into the clinic with its proprietary Dicer substrate technology.

Having achieved 90-percent knockdown in 24 hours after a single dose in metastatic mouse melanoma and other tumor models, James Jenson, CEO and co-founder of Dicerna, says recent results have exceeded expectations, and as a result, the company has initiated an in-house clinical program.

"We're getting knockdown in multiple hard-to-knock-down tissues at dosing levels of tens of milligrams per kilogram using Dicerna nanoparticle substrates," he says.
The in-house program is developing a dicer-substrate based drug that will target an undisclosed cancer and should be in the clinic within 18 months. There are validated targeted drugs on the market for the specific cancer type, but resistance to them frequently develops, Jenson notes. Dicerna's plan is to come in behind and "blow them away," he adds.

Dicer is a critical enzyme involved in the RNAi gene silencing cascade and acts earlier in the pathway, preparing double-stranded RNA for processing. Dicer then hands off these small RNA molecules to the mature gene silencing complex (RISC). Dicerna's synthetic Dicer Substrate siRNA (DsiRNA) molecules are 25 or more base pairs in length, feed into the RNAi pathway upstream of 21mer first-generation molecules and take advantage of this natural and early entry point. Jenson says that this results in greater potency, with single-digit nanomole inhibition, the ability to extend to multiple targets beyond KRAS and potent knockdown in solid tumors and well as hemapoetic tissues such as spleen and bone marrow.

Under the agreement, Ipsen's expertise in peptide engineering will be combined with Dicerna's exclusive Dicer Substrate technology to develop innovative molecules as potential therapeutic agents.

"Our longer molecules have 'handles' that are clipped off and replaced with targeting moieties," says Jenson. "Ipsen peptides will target receptors with payloads and bind, carry and deliver the payload to the target cell."

The research collaboration aims to yield two products that will be shared equally between the two companies. Jenson notes that in addition to nanoparticle deliveries, Dicerna's integrated drug delivery system (IDDS) will also be used in the research.

"Combining Dicerna's Dicer Substrate technology with Ipsen's innovative peptide technology that can target specific cell types of interest and mediate intracellular delivery of DsiRNA will enable us to jointly explore a number of therapeutic programs in the areas of oncology and endocrinology," says Claude Bertrand, executive vice president and chief scientific officer of the Ipsen Group. "We believe that this collaboration brings together two leading companies with unique and complementary technology platforms which could potentially lead to the discovery of breakthrough DsiRNA-based therapies."
The companies will conduct collaborative research aimed at identification of new DsiRNA-based therapies with targeted delivery, superior potency and extended duration of action. Both companies will contribute their breakthrough technologies to the joint research collaboration. Dicerna and Ipsen may collaborate further to move the programs discovered under this partnership into development and eventual commercialization.

Ipsen is a global biotechnology specialty care group with total sales in excess of $1.3 billion in 2009, and total worldwide staff of more than 4,400. Its strategy is based on fast-growing specialty care drugs in oncology, endocrinology, neurology and hematology, and primary care drugs, which significantly contribute to research financing. This strategy is also supported by an active policy of partnerships. Almost 900 people are dedicated to the discovery and development of innovative drugs for patient care. In 2009, R&D expenditure was close to $269 million, representing more than 19 percent of total group sales.

"We are very excited to partner with Ipsen on this exclusive research collaboration. This agreement further advances our discovery efforts and provides us with the opportunity to develop Dicer Substrate siRNA therapies and targeted drug delivery systems while working with a partner who brings a unique peptide technology platform to the collaboration," Jenson adds. "This is the second significant partnership with a major biopharmaceutical company that we have entered into in 2010, further validating our next-generation Dicer Substrate technology and our unique ability to generate a greater number of more potent gene silencing molecules."

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