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Wednesday, October 31, 2007

Dicerna Crashes RNAi Party

Life often imitates art, as the saying goes.

In “This Is Spinal Tap,” the classic rock and roll mockumentary chronicling the eponymous band, guitarist Nigel Tufnel famously brags that his amplifiers, unlike conventional ones that max out at a volume of ten, were specially designed to go “one louder.”

“These go to eleven,” he deadpans.

IN VIVO Blog has learned that in the world of RNA interference (RNAi), a new company aims to make some noise of its own not by going louder, but longer, while at the same time circumventing the IP barriers to entry in the exciting field.

Dicerna Pharmaceuticals Inc. is based on technology called Dicer substrate small interfering RNAs developed by co-founders John Rossi, PhD, from the City of Hope National Medical Center’s Beckman Research Institute and Mark Behlke, MD, PhD, from Integrated DNA Technologies Inc. (IDT). Dicer substrate siRNAs differ from traditional siRNA employed by companies like Alnylam Pharmaceuticals and Merck & Co.’s Sirna Therapeutics in that they are slightly longer oligonucleotides—between 26 and 30 base pairs (bp) versus 21bp for standard siRNA—which then get trimmed down to size once inside the cell.

Dicerna is expected to announce its $13 million Series A, which will be led by Oxford Bioscience Partners, at some point in November.

Dicerna hopes that its longer molecules not only confer an IP workaround strategy in the hot area of RNA interference therapeutics, but also a pipeline of highly potent drug candidates that will pique the interest of quite a few Big Pharma that have been so far left out of the increasingly expensive but important RNAi arms race.

The seminal patent licensed by both Alnylam and Sirna named after RNAi pioneer Thomas Tuschl, PhD, only covers isolated double-stranded oligonucleotides from 19 bps up to 25 bps, Dicerna co-founder and chief executive James Jenson tells IN VIVO Blog. Tuschl’s landmark work in RNA interference was conducted in Drosophila, says Jenson. “Beyond 21mers the activity of siRNAs drops off in Drosophila, which is reflected in the Tuschl patent applications, and the literature at the time teaches that limitation. It’s where the streetlight was shining and where the research was focused,” he says.

The Rossi and Behlke IP, owned by City of Hope and IDT, allows an adjacent doorway into RNAi from an IP perspective, Jenson claims. What’s more, Rossi and colleagues somewhat surprisingly discovered, in mammalian cells longer double-stranded RNAs worked better than the 21mers thought to be optimal under Tuschl; 26-30mer oligos are “typically five to ten fold more potent,” says Jenson, perhaps resulting in a longer duration of action that has been demonstrated in vitro by Rossi, et al. “In a technology where adequate delivery has been a challenge, the increased potency could be important,” says Jenson. The researchers have been publishing their results with Dicer substrate siRNA since 2005 in journals such as Nature Biotechnology and Nucleic Acid Research.

The process of RNA interference begins when the Dicer enzyme cleaves double-stranded RNA into 21bp oligonucleotides, which are then incorporated into the so-called RNA-induced silencing complex (RISC); RISC then targets messenger RNA sequences determined by the siRNA sequence. Because one end of Dicerna’s 30bp Dicer-substrate siRNAs will be clipped by Dicer and removed to form the active 21mer, various targeting agents can be attached to the non-coding end of the molecule, says Jenson.

Jenson has been busy reaching out certain investors and potential partners since completing an agreement with City of Hope in late September on a license to the IP. He’s been joined by Dicerna chairman and co-founder Douglas Fambrough, PhD, a general partner at Oxford and a former director of, and early investor in, Sirna.

Dicerna's IP hasn’t gone completely unnoticed; in fact, Dicerna isn’t even the first company to license it. Nastech Pharmaceutical Co. gained a more limited license to the technology in late 2006; it holds exclusive rights to the Dicer-substrate technology for five undisclosed targets and broad, nonexclusive rights to siRNAs directed against all mammalian targets (subject to undisclosed limitations).

Fambrough says that Sirna held discussions to gain access to the technology as well, but “for whatever reason those talks never went anywhere. When we sold the company to Merck I was aware of the IP and Jim Jenson and I had been talking about doing something in RNAi for oncology, but we thought, why just go after oncology?”

Dicerna now has an exclusive license for all remaining rights on the Dicer-substrate IP, says Fambrough, and previous licensees won’t affect Dicerna’s plans or the value of the IP to potential acquirers, partners or investors, he maintains.

Nevertheless, it’s still early days. “Only recently have people woken up to this additional doorway into the RNAi space,” says Jenson. In part, he suggests, that’s because Alnylam and Sirna, the companies with access to the Tuschl IP, have done such a good job convincing the world that theirs is the only pathway. Those two firms have certainly been at the forefront of the field, consolidating IP early and almost exclusively garnering the attention of Big Pharma. And some observers feel the patent battles—which may heat up as product candidates inch toward the market—have barely begun.

Alnylam’s early deals gave a small handful of companies, led by Novartis, an early entry into the field. Merck broke new ground in RNAi dealmaking when it acquired Sirna in late 2006 for $1.1 billion. Most recently, Alnylam has upped the ante with a broad strategic alliance with Roche, whereby Roche has paid $331 million for a non-exclusive license to Alnylam’s platform and IP over several therapeutic areas.

Dicerna hasn't specified a therapeutic focus, reflecting perhaps the reality that the firm’s initial targets will likely be dictated by its future pharmaceutical partners as much as by any internal strategy. Those pharma alliances will almost certainly be struck with one eye on an M&A exit.

"Ultimately the technology belongs in a large pharmaceutical company, and we would like to partner early on in ways that do not jeopardize an eventual acquisition and in ways that aren’t overly dilutive,” says Jenson. “There are other approaches out there but few if any that will allow you to compete with Tuschl this way.”

The full text of this article will appear in the November issue of START-UP.

1 comment:

Pete Shuster said...

Great summary on the Dicerna potential. I wanted to mention that my customers have used IDT's for delivering 27mer DsiRNA to the CNS and have published results. This platform is very promising for gene expression analysis and drug discovery.

see: Louis Doré-Savard, Geneviève Roussy, Marc-André Dansereau, Michael A Collingwood, Kim A Lennox, Scott D Rose, Nicolas Beaudet, Mark A Behlke and Philippe Sarret. Central Delivery of Dicer-substrate siRNA: A Direct Application for Pain Research. Molecular Therapy (2008); doi:10.1038/mt.2008.98


"In this study, we demonstrate the efficacy of 27-mer DsiRNA in reducing the expression of a specific G-protein coupled-receptor (GPCR) gene in rat spinal cord and DRG. Low doses of DsiRNA formulated in i-Fect, when administered by IT injection, induced a sustained reduction in the neurotensin receptor-2 (NTS2) GPCR mRNA and protein levels for 3–4 days. The reduction in NTS2 resulted in the expected behavioral changes in nociception. No apparent toxicity or nonspecific side effects were exhibited during the study period, and our results overall highlight the feasibility of using DsiRNA in pain research.”