By Doug Macron
About a year and a half after its founding, siRNA delivery firm Qualiber has secured a $30,000 low-interest loan from the North Carolina Biotechnology Center to help it with non-scientific startup activities.
Advancing its technology, however, will require additional funding, and the company hopes that an ongoing technology-evaluation deal with a bigger partner will translate into a full-fledged collaboration and provide partnership revenues.
Qualiber was spun out of the University of North Carolina, Chapel Hill, to commercialize a drug-delivery technology developed by company co-founder and UNC researcher Leaf Huang.
The technology as originally developed was comprised of a protamine/DNA/siRNA core surrounded by two cationic lipid layers. According to a grant Huang received from the National Cancer Institute earlier this year, when the nanoparticles were incubated with a polyethylene glycol-phospholipid conjugate, the outer bilayer was stripped off, but the inner bilayer survived with a high degree of pegylation.
“The densely packed surface PEG formed a brush protection layer to shield the cationic charges of the nanoparticles and reduced opsonization by serum proteins,” the grant's abstract notes. “The result was a very low degree of uptake by the liver and the spleen, and a very high level of tumor uptake” that was facilitated by the addition of targeting ligands.
Despite their effective delivery to tumors, the nanoparticles failed to deliver their payloads effectively, with most of the siRNAs sequestered in endosomes, according to Qualiber President and CEO Anil Goyal.
Huang then discovered that complexing the siRNA with calcium phosphate rather than protamine could sidestep this problem, Goyal told Gene Silencing News. In experiments in Huang's lab, the calcium phosphate dissolved within the acidic environment of the endosome, increasing osmotic pressure and causing it to burst, thereby releasing the siRNA payload.
“The shorter the siRNA is in the endosome, the less likely it is to get degraded,” he said. By using the new approach, dubbed lipid-coated calcium phosphate, or LCP, “we are delivering more effectively most of the siRNA to the cytoplasm.”
In a paper published in early 2009, Huang and colleagues demonstrated that this approach could silence 70 percent of luciferase activity in cultured tumor cells and about 50 percent of luciferase activity in a xenograft model, with negligible toxicity.
Qualiber has followed up on these findings, and Goyal said that the company has been able to achieve tumor-growth inhibition in vivo using “20-fold less siRNA than what has been reported by other investigators in the space.”
Specifically, in a mouse model of lung cancer, the company halted tumor growth using siRNAs against three targets — HDM2, c-Myc, and VEGF — at doses as low as 0.36 mg/kg with the LCP technology, he said. Importantly, the LCPs appear to avoid the liver and spleen, with about 95 percent of the particles ending up in tumor tissue.
With these data in hand, Qualiber has already found one company interested in evaluating the delivery approach using its own siRNAs against cancer-related targets, and is in discussion with “several” others about similar arrangements, Goyal said.
“We will get a little bit of funding … [through these] evaluation agreements,” he noted. “Once we pass that work, I would anticipate we actually sit down and work out a larger collaboration where we become one of the delivery solutions they pursue in their [drug]-development path.”
Importantly, possible collaborations will provide Qualiber with funding to get its in-house, non-RNAi programs underway — something that is particularly needed given the difficulty the company has had securing venture capital investment.
He noted that the company was making progress with investors last year until the RNAi field was rocked when two high-profile pharmas, Pfizer and Roche, decided to stop work on the technology (GSN 11/18/2010 & 2/3/2011).
“We're still trying to recover from that to get [venture capital] investors interested,” Goyal said. VCs “are willing to invest in existing portfolio companies that are working in the [RNAi] field … but new company investment has been very difficult.”
The low-interest loan from the North Carolina Biotechnology Center will buy Qualiber some breathing room, but notably it cannot be used for scientific purposes, such as the salaries of researchers. The company hopes to secure a small business innovation research grant from the National Institutes of Health to enable it to hire its first in-house scientist in the near future, he added.
Should Qualiber be able to find an RNAi partner for the LCP approach, it hopes to then begin work on using the technology to deliver small-molecule chemotherapeutics as part of its internal drug-delivery programs.
“We are not trying to be an siRNA company,” Goyal said. “There would be a lot of expertise we would need to build that is already present at big pharma and existing RNAi companies. We are happy to be on the delivery end of things [for RNAi] and build a [drug-development] business with small molecules."
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