By Doug Macron
As the focus of RNAi drug developers increasingly sharpens on delivery, startup Carigent Therapeutics is aiming to make a name for itself in the field with a novel technology it claims is as effective as other approaches but has a superior safety profile.
Carigent was established in 2007 as a spinout of Yale University, and holds a portfolio of exclusively licensed intellectual property from Yale and Cornell University protecting its core delivery technology, President Seth Feuerstein told RNAi News this week.
According to Carigent, its delivery technology involves attaching "high densities of application-specific molecules to the surfaces of biodegradable, polymeric particles ranging in size from tens of nanometers to hundreds of microns."
"We start with an FDA-approved backbone … and can do high loading in non-cationic polymers of oligonucleotides like RNAi [agents], showing in vivo that we can deliver them effectively," Feuerstein said. "We get previously unseen levels [of oligo loading] — levels that are considered more than enough to achieve efficacy in humans … and are continually improving."
Targeting the nanoparticles to specific tissues or cells, meanwhile, can be achieved by attaching targeting ligands to the particles' surfaces.
Importantly, the polymer nanoparticles are "at least an order of magnitude less toxic than cationic vehicles," he noted. "We use [polylactic-co-glycolic acid] primarily … [which] has numerous uses in humans and is very safe … having been used for everything from depo-drug injections to microsutures."
In May, Carigent co-founder and Yale researcher Mark Saltzman published data in Nature Materials describing the loading of PLGA nanoparticles with siRNAs, which could then be delivered topically to the vaginal mucosa with significant and sustained target-gene knockdown.
The paper, Feuerstein noted, served as a strong proof of concept for the technology and resulted in collaborations with undisclosed partners interested in taking the findings further. But he stressed that at this point, Carigent has "achieved far higher loading levels and [has] additional layers of technique and intellectual property on top of" what was described in the publication.
As a result, the company has been able to ink a number of technology-evaluation deals with various big-, medium-, and small-cap pharma and biotech companies, although these, too, remain undisclosed, he said. The collaborations, he added, "run the gamut" and are focused not only on siRNAs, but also microRNA mimics and antagonists, and "modified, siRNA-like" oligos.
Feuerstein said that Carigent's technology has received so much interest mainly because of the safety of the polymers it uses. "While people want to see knockdown, they also want to see low toxicity levels," he said. And although PLGA, for example, is not a secret, "no one thought you could load a lot of oligos into" these kinds of particles.
"We're using material that is really well-known, but most people in the RNAi field don't work with it because everyone thought you should be working with cationic lipids, primarily," Feuerstein said. As a result, "there's a little bit of a learning curve [for] the people we work with.
"When we meet with people, they just say, 'Really? We didn't think this was even possible,'" he said.
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And since the materials Carigent uses are known to be safe, taking a unique approach to an all-too-common problem in a field "heavily loaded with lipid people" has proven appealing to potential partners, he noted.
Thus far, Carigent has generated positive both in vitro and in vivo data, conducted in-house and through partnerships, Feuerstein said, adding that he is optimistic that at least one of the company's tech-evaluating deals will blossom into a full-fledged research and development alliance within the next 12 months.
At the same time, Carigent's six full-time scientists are advancing the firm's internal pipeline programs, which is expected to yield its first drug candidate sometime in 2010. Feuerstein declined to provide specific details about that work, but said that central nervous system disorders are a key near-term focus "because there are such well-identified genetic targets, and our particles apparently knock them down" after systemic delivery.
"We really think it's interesting that, for instance, using all FDA-approved materials, we can get to the brain" by ostensibly crossing the blood-brain barrier, he added.
Yet "raising the kind of capital that you need to move full steam ahead with a clinical program doesn't seem to be the obvious best use of shareholder equity in the current environment," Feuerstein said. "Plus, [the fundraising process] is a distraction from scientific progress."
As a result, the company is taking a measured approach to its in-house research, applying its technology to areas where system delivery has heretofore been a challenge, like the CNS, as well as to areas of interest to potential collaborators, he said.
"We realized [that] you should actually be generating, for instance, hepatic data because big pharma is very interested in [it]," he said. "So even though everyone is already doing it, to show [companies data on] indications that aren't a focus of theirs doesn't necessarily lead to partnerships because they've already made large investments in particular therapeutic fields."