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Protiva Looks to Apply its Plasmid Delivery Technology, Already in the Clinic, with siRNAs

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As interest in RNA interference continues growing, so too does the number of companies looking to apply their technologies to the sector. Among these is Protiva Biotherapeutics, a privately held Seattle-based biotech firm that just recently began looking at using its DNA-based protein delivery technology with siRNAs.

The technology is known as SNALP — short for stable nucleic acid lipid particle — and Protiva started out developing it as a way to deliver protein-encoding plasmids. But about six months ago, the company became interested in applying SNALP to siRNAs, Protiva president and CEO Mark Murray told RNAi News.

“We knew that we could encapsulate and deliver plasmids, and we know that we can build those plasmids to express anything,” he said. “So we then turned our attention to see if we could encapsulate and deliver the siRNA duplexes.”

According to Murray, SNALPs are essentially “a lipid bilayer with an aqueous core, and they’re manufactured in a novel way that allows us to form the particle as we encapsulate the nucleic acid payload.” Specifically, the nucleic acid is encapsulated by cationic and fusogenic lipids, which are surrounded by a polyethylene glycol (PEG) coating. This coating prevents the clearance of the positively charged cationic lipid from the bloodstream, thereby boosting the circulation time of the SNALP, Murray said, adding that the company’s research indicates that “over 15 to 20 percent of the injected material remains intact and in circulation at 24 hours following intravenous administration.”

Murray noted that the comp- any is continually evaluating different lipids for use in SNALPs in order to boost efficacy. “The lipids in these formulations are not necessarily static,” he said. “We’re continuing to optimize the lipid chemistry so we get more and more potency out of the formulation.”

Protiva is primarily looking into using SNALPs for oncologic indications, namely distal tumors. According to Murray, SNALPs are particularly effective in entering cancer tissue from the bloodstream because of the rapid manner in which tumor angiogenesis occurs. “Normal blood vessels are these nicely formed tubes with an endothelial cell lining that will restrict what leaves the blood vessel and goes into the tissue,” he said. “If you look at a tumor, the vasculature is disorganized and there are gaps between the endothelial cells. In many cases, there is a lot of exposure of the tumor directly to the vessel.”

Taking advantage of the resultant vascular leak, Protiva expects that if SNALPs can be kept in circulation long enough, they will “essentially percolate out, accumulate at sites where these vessels are leaky.”

Murray said that the company’s approach to testing SNALPs “is to create a tumor in an animal — on the hind flank generally — administer the product through the tail vein, and then measure the circulation time and the accumulation in the tumor, which is several centimeters away from the injection site.” Protiva’s data indicates that between 12 and 15 percent of the administered SNALP dose is present in such distal tumors at 24 hours, he noted.

All this preclinical work has been conducted using plasmids and siRNAs, Murray said. “We can … encapsulate siRNA to a very high efficiency — over 95 percent of the input material is encapsu- lated. The particles have a long circulation life in animals, they will accumulate in the tumor, and we can down-regulate the target protein in the tumor in vivo by intravenous administration.”

Protiva also began very recently a phase I trial wherein the SNALP technology is being used to deliver plasmids encoding a cytotoxic protein to tumors. “We refer to [this application] as targeted therapeutic proteins, because we can get selective expression in tumors and not in normal tissue,” Murray said. And while this study is not directly related to RNAi, it could yield some insight into how the technology would work with siRNAs. “We would expect, for example, a plasmid expressing short hairpin RNAs to behave exactly the same way” as ones expressing proteins, he said. “Sort of a proof-of-principle, if you will.”

Protiva is in the process of looking for a partner for the SNALP technology, Murray said, namely a partner that is “more involved in the identification of targets and the development of the siRNA reagent,” but is lacking the expertise necessary to get the oligos where they need to go. “We’re looking to fill the delivery gap.”

Discussions with possible partners are underway, Murray said, but these are “early-stage.” As for those companies interested in Protiva’s technology but not a partnership — they’ll have to look elsewhere. Murray said that Protiva probably would not consider out-licensing the SNALP technology, because “we’re interested in a partner being successful. We know a lot about how to build these particles and manufacture them, the whole product development side of the particle, and we think we need to be involved in its support in order to make a development relationship go.”

Even if Protiva is unsuccessful in finding a partner in the near-term, Murray said that the comp- any is intent on moving an siRNA-based SNALP into the clinic within 12 to 18 months. “The platform itself has gone through the whole preclinical development, IND development … so we think that we can very rapidly move an siRNA product into the clinic, and we’re looking quite seriously at doing that [by ourselves].”

To do so would, of course, require capital, so it’s no surprise that Protiva is in the midst of a Series B round of financing. Murray said that the company raised roughly $10 million in its Series A fin- ancing in late 2001, and now is looking for another $15-$20 million.

Commenting on the process of looking for funding, Murray said “it’s tough. We have strong insiders who are committed, but it’s tough finding new people.”

The company is, however “getting a few nibbles.”

—DM

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