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As RNAi Rx Efforts Progress, Some Companies Look to Use Technologies in Other Areas

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By Doug Macron

As RNAi drug candidates advance from the clinic toward the marketplace and begin to fulfill the gene-silencing technology's therapeutic promise, many in the space have kept a tight focus, limiting themselves to a few key pipeline programs (GSN 3/11/2010).

In addition to Rosetta Genomics, which has launched its Rosetta Green unit to use microRNAs in plant biotechnology (related story, this issue), a handful of others have begun testing the waters outside their core areas of expertise and are exploring the possibility that their respective technologies may have value beyond RNAi-based medicines.

Alnylam Pharmaceuticals, for instance, has long been the field's highest-profile player, building an extensive portfolio of RNAi drug-related intellectual property and moving three products into human trials.

Last November, however, the company announced that it had established a new initiative, dubbed Alnylam Biotherapeutics, to use its RNAi know-how to improve biologics manufacturing (GSN 11/19/2009).

Alnylam said at the time that it has developed proprietary delivery lipids that enable the efficient transfection of siRNAs into Chinese hamster ovary cells — commonly used in the production of biologics — when grown in suspension culture. The company also said that its studies have shown silencing certain target genes involved in certain CHO cell apoptotic and metabolic pathways led to a 40 percent to 60 percent improvement in cell viability as compared with untreated cells.

Earlier this year, Alnylam released data showing that CHO cells treated with the siRNAs experienced a roughly 80 percent reduction in the mRNA levels of the apoptotic regulators Bax and Bak, as well as the metabolic enzyme lactate dehydrogenase.

Treated cells also showed a greater than 65 percent decrease in LDH enzyme activity; an approximately 90 percent decrease in caspase 3 activity, a downstream mediator of apoptotic cell death; and a greater than 90 percent increase of viable cell density, the company reported.

While Alnylam Biotherapeutics remains an early-stage effort, a company official in May said that industry response to the unit has been "robust," and deals for the use of its technologies for biologics manufacturing "could be quite near-term" (GSN 5/13/2010).

Also looking at new opportunities is Marina Biotech, formerly MDRNA. After transforming itself from the intranasal drug-delivery firm Nastech Pharmaceutical just two years ago (GSN 5/8/2008), the company has steadily built up a presence in the RNAi drugs space.

To date, the firm has signed technology-licensing deals with Roche and Novartis, and has established a pipeline that includes a program in familial adenomatous polyposis, which was acquired through the purchase of Cequent Pharmaceuticals (GSN 4/1/2010) and is poised to enter phase I testing this year, and earlier-stage programs in bladder and liver cancers.

However, in June, MDRNA announced that it had acquired the diagnostic rights to RiboTask's unlocked nucleobase analog technology, which it had previously licensed for therapeutic applications (GSN 6/10/2010).

In an interview with Gene Silencing News, Marina President and CEO Michael French said that the deal reflected the company's consideration of entering the companion diagnostics and miRNA therapeutics fields.

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The UNA technology, in conjunction with Marina's conformationally restricted nucleotide technology, could be used to develop molecular probes for diagnostics, French said, adding that the two approaches could also enable the development of miRNA-targeting compounds.

Still, he stressed that Marina was just "scratching the surface of the whole diagnostic play" and had not yet determined how best to approach the space. At the same time, miRNA therapeutics remain a just a possibility as the company focuses on its near-term initiatives.

RXi Pharmaceuticals, meanwhile, is also weighing the value of its RNAi molecules for miRNA-targeting applications.

In April, the company announced two separate deals with miRNA drug firms — Mirna Therapeutics and Miragen Therapeutics — to evaluate its proprietary self-delivering rxRNAs as miRNA mimics (GSN 4/15/2010).

Under the first deal, RXi and Mirna will evaluate whether rxRNAs can be used as miRNA mimics against targets in oncology, Mirna's core disease area. In the second arrangement, RXi will work with Miragen to develop rxRNAs as therapeutic miRNA mimics for cardiovascular and muscle diseases, fields in which Miragen specializes.

While RXi has since announced that its primary focus for the near term will be to develop RNAi drugs for dermal and ocular disorders (GSN 6/17/2010), the company's President and CEO Noah Beerman told Gene Silencing News at the time the deals with Mirna and Miragen were struck that they enable his company to "leverage the [sd-rxRNA] technology into some really exciting areas."

RNAi drug developers aren't the only ones looking for new opportunities, however.

Last November, reagent firm Bioo Scientific announced that it had established a new division called Bioo Therapeutics to direct its drug-delivery, antibody, and small-molecule technologies toward the development of treatments for cancer and other diseases (GSN 11/19/2009).

Although Bioo Scientific developed its technologies for research purposes, the company saw potential in the therapeutics space, Lance Ford, Bioo Scientific’s vice president of research and business development, told Gene Silencing News last year.

At the top of the list is its so-called Targeted Transport Technology, which involves joining a carrier agent to a monoclonal antibody to produce a conjugate, which is then loaded with an RNAi molecule such as an siRNA or miRNA mimic.

A month later, Bioo Therapeutics announced a collaborative research agreement with Texas Tech University to develop methods to deliver siRNAs into T cells (GSN 12/3/2009), and the company has an ongoing collaboration with Mirna to develop a mimic of miR-34 as a treatment for cancer.

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