By Doug Macron
EGEN last week announced that it has extended a collaboration with SurModics to develop a long-term controlled-release system for therapeutic siRNA delivery.
The company is not yet certain which diseases would be most amenable to such early-stage technology, an official told Gene Silencing News this week. However, it plans to apply a "bottom-up" strategy wherein the delivery route determines the indication it pursues — an approach the company is also using with its more advanced program delivering siRNAs to the lung.
Founded as a gene therapy developer with the name Expression Genetics, EGEN has an ovarian cancer treatment in phase I development comprising a human interleukin-12 plasmid formulated with a lipopolymer-based delivery vehicle.
Khursheed Anwer, EGEN president and CSO, noted that when gene therapy was a hit field in the early 1990s, companies in the space would often pursue particular indications based on their market potential and "kind of force the technology into that area.
"That resulted in a lot of failures, so we thought, 'We'll go from the bottom, up,'" he said. "We'll see which delivery system route works the best, and that will [define] our application."
Data showed that the delivery agent worked best when administered intraperitoneally, he said. "Then the question was, 'What's the best indication to go after?'" Given that the majority of ovarian cancer metastasizes into the abdominal cavity, the company focused on that disease.
When RNAi came to the forefront as a potentially powerful therapeutic modality, EGEN began investigating whether the delivery agent used in its ovarian cancer candidate could be used to administer siRNAs.
"We began to test our gene-delivery carriers for RNAi … [but] were not getting good knockdowns in vitro," Anwer said. "We played for about six months to a year with the systems we had, but we just didn't get more than 30 or 40 percent knockdown. So we changed our strategy … to make a fundamental change and come up with a different type of delivery approach."
The result was the company's so-called TheraSilence lipopolyamine molecules that can be modified chemically and functionalized for siRNA delivery. "Sure enough, [these] molecules began to give us 90 percent knockdown in vitro," he noted.
After some setbacks with in vivo testing, "we played with the formulation and made some more molecules, modifying our lipid backbone and … we able to get about 50 [to] 60 percent knockdown in the lung," with low toxicity, when delivered intravenously into mice, Anwer explained.
Experience in gene therapy suggested that the lung delivery might be related to a first-pass effect, he added, "but we've done enough experiments to convince ourselves that [this is not the case]. There is something in the formulation that is unique to lung," although the exact reason remains unclear.
Nonetheless, EGEN was encouraged by the data since "there is not much lung data … out there," and it has begun animal testing to determine what indications would be most amenable to the technology.
The firm has identified the cell type in the lung that most readily takes up the TheraSilence siRNAs, although Anwer declined to provide specifics, and is working to "demonstrate the benefit of ... [the gene] knockdown," he said. "The next goal is to … pick a therapeutic target and show benefit, whatever the disease is."
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Anwer noted that the effort could yield an investigational new drug application filing within a year and a half to two years.
Meanwhile, EGEN continues to work with SurModics, which manufactures the lipopolymer used with the ovarian cancer drug, under a feasibility collaboration initiated about a year ago to see whether SurModics' controlled-released systems would be compatible with EGEN's siRNA delivery agents.
Previously, the companies developed a hydrogel delivery system that combined EGEN's TheraSilence molecules with SurModics' maltodextrin-based polymer platform. According to data released earlier this year, the system enabled "long-term controlled release of bioactive siRNA/lipopolyamine complexes out to 100 days in vitro."
Based on these encouraging data, they have extended their collaboration with the goal of establishing in vivo proof of concept of the controlled-release system for local siRNA administration, Anwer said.
As with its other drug-development efforts, EGEN is going to let the delivery system help define the indication.
"Right now, the results [in hand] are from cell culture and we really don't know" where the approach would be most applicable, he said. "We will look into different delivery modalities and the [one] that fits the best would be the source for the application."
As it stands now, "some sort of depot in a solid tissue such as a tumor would be a logical thing to do," Anwer added.