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CalTech Spinoff Insert Therapeutics Looks to Use RNAi in Inhalable Drugs, Medical Devices


Delivery is perhaps the biggest hurdle for those racing to develop RNAi therapeutics — so much so that developing solutions to the problem has become a virtual cottage industry. Companies including Intradigm and Mirus have been working on delivery for some time, while others, such as newcomer Nastech, are just starting to get in on the action (see RNAi News, 2/6/2004).

One company, Insert Therapeutics, has been examining the issue for years and, according to founder Mark Davis, has the intellectual property to set it apart from all the others. But whether the company — which is applying its delivery techniques to a variety of pharmaceutical compounds — will succeed in the RNAi arena appears to hinge on its ability to attract partners.

Davis, a researcher at the California Institute of Technology, established Insert in 2000 in order to commercialize polymeric delivery technologies he developed at CalTech. Davis is also the lead inventor on a patent application — number 20030157030 — entitled “Methods and Compositions for Therapeutic Use of RNA Interference,” which covers RNAi constructs that have been formulated as microparticles made from biodegradable polymers. (A follow-on patent application was published on April 1 [see IP Update, p. 3].)

This application was filed on Nov. 4, 2002 and claims the benefit of priority from a provisional application filed on Nov. 2, 2001. “I believe it’s the first one [covering] any delivery of RNAi,” Davis told RNAi News. “There was some really nice stuff that came out of Mirus and some other places, but those were naked [oligonucleotides].”

Davis, like many others, is working on developing systemic delivery methods for RNAi molecules. “We’re basically in small animal models,” he said. “We’ve worked on two targets: One is hepatocytes and the other is tumors — these are standard targets.”

But what is not standard about Davis’ work, which he said is being conducted jointly by CalTech and Insert, is its potential with less traditional routes of administration.

“When you mix the polymer systems we’ve been working with with nucleic acids … [you can] make free-flowing powders of these [by using a vibrating orifice aerosol generator], so if you wanted to do inhalation with them” you could, he said. Already, inhalable formulations have been put together and appear to be deliverable to specific areas of the lung.

Testing of inhalable products, however, has been limited [to] an Andersen Impactor, Davis said. “It’s a device that simulates your lung … that [can be used] to get an idea if you’re going to get deep lung penetration, or [delivery] up in the trachea,” he explained. “We just use an Andersen Impactor as a way to tell us whether we’re making the particles able to target various sections of the lung.”

The next step would be to evaluate the inhalable RNAi drug formulations in animals, but Davis said that this is something that would require an industry partner. “We’re looking for partners, [because] we can make particles, we can test their sizes, but we don’t have animal models in house to test” this, he said.

This limitation is also hanging over Davis’ work with RNAi-coated matrices that could be turned into such devices as drug-eluting stents or catheters, another embodiment of the Insert polymer technology.

“We’ve been able to … make composites of [polymers and nucleic acids] with other types of material that would be applicable to make degradable coatings and so forth,” Davis said. “We’ve actually been able to show that you can you can get [the composites], you can get them to work together as a system, and do the right kinds of things that they’re going to need [to do] in those types of configurations.”

This has been accomplished by putting the materials on various surfaces and examining how they act, he said. “If you want cells to adhere to [composites], you can make cells adhere to them. If you want cells to penetrate them, you can do those tests.

“It’s more than just saying: ‘I want to do it,’” Davis added. “We’ve actually shown that these components all can come together and do those pieces of the puzzle. What we need to do now is go into a real animal model to see if you can have an effect on the disease state,” he added.

But to go as far as making, say, an RNAi drug-coated stent and testing it in vivo, Davis said that the resources are lacking. “We don’t have animal models for those — we would need to partner [on this], as well,” he said.

This is a task that has fallen to Insert, Davis said.

“All of the original [research papers] were from my group at CalTech,” he said. “As ones are coming out now, they’re transitioning from CalTech to Insert, and [the people at Insert] are the ones who are looking for partners for commercialization.”

Davis declined to comment specifically on any negotiations that Insert may have had with possible collaborators, but did say that the company has “had discussions with many of the people who are the players in RNAi … and also they have had discussions with several device companies.”

John Petrovich, Insert’s COO, was unavailable for comment.

Davis noted that Insert’s former CEO, Leonard Borrmann, recently left the company and a replacement has yet to be found.

— DM

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