Employing the tools of gene therapy, Sunnyvale, Calif. startup Avocel is determined to make a place for itself in the RNA interference therapeutics arena.
By the end of next year, the company wants to file an application for an RNAi-based investigational new drug to treat hepatitis C, and to start a clinical trial by early 2006, according to Sara Cunningham, a company co-founder and its vice president of intellectual property and business development.
To achieve these goals, Avocel is using technology developed by Mark Kay, a professor of pediatrics and genetics at Stanford University School of Medicine who specializes in gene therapy for hemophilia and hepatitis. In adult mice, he successfully suppressed the expression of HBV and HCV genes by RNA interference.
“That was the earliest demonstration in a post-embryonic mammal of what we understand to be RNAi,” Cunningham told RNAi News.
Kay published a paper in Nature in 2002, showing that he was able to suppress the expression of an HCV gene by injecting siRNA or a plasmid coding for shRNA into the liver of adult mice. In an article in Nature Biotechnology in 2003, he showed that shRNA expressed off a plasmid could inhibit replication of an HBV plasmid in mice.
Kay, who has experience in developing vector systems for gene therapy of hemophilia, told RNAi News that “the hepatitis work has followed behind [hemophilia] because up until RNAi, the things that we had tried … just didn’t work well enough. Now, at least in these pre-clinical models, RNAi looks very promising.”
Avocel makes a point of preferring expressed RNAi, where the DNA template is delivered by a viral vector, over delivered RNAi, where synthetic RNA is injected.
The gene therapy approach has several advantages, according to Cunningham: It is the easiest, if not the only, way to get RNA into liver cells, and the vectors Avocel uses — adeno-associated viruses, for example — have already been tested for safety and are currently used in gene therapy clinical trials. In addition, she said, expressed shRNA comes closer to how RNA interference happens naturally in a cell than delivering synthetic siRNA does.
Avocel has licensed two of Kay’s patent applications from Stanford University: US Patent Application 20030153519, entitled “Methods and compositions for RNAi mediated inhibition of gene expression in mammals,” and US Patent Application 20030139363, “Methods and composition for RNAi mediated inhibition of viral gene expression in mammals.” Both claim priority from a provisional patent application filed on July 23, 2001.
Except for reagent sales, the company holds exclusive rights to all commercial use of these patent applications with regard to expressed RNAi, and shares co-exclusive rights with Alnylam Pharmaceuticals for delivered RNAi.
Avocel chose hepatitis as its first target not only because of Kay’s expertise, but also because of the medical need. There is currently no vaccine for hepatitis C, and more than half of the patients don’t have a long-term response to currently available drugs, according to Kay. And even though there is a vaccine for hepatitis B, the current drugs sometimes fail, he said.
One advantage of an RNAi therapeutic over a single small-molecule drug, Cunningham said, is the possibility to target several hepatitis viral genes at the same time.
But the company still has a long way to go before it is ready for a clinical trial. “The next step is to design the most efficacious sequences against hepatitis C and B, and then to start to look at these in different animal models, and start delivering these…in a way that would be clinically relevant,” said Kay. The plan is to have a clinical candidate for hepatitis C ready by this fall.
Longer term, Avocel is also interested in other disease areas amenable to RNAi, for example congestive heart failure, other infectious diseases, and cancer, and is looking for collaborations in new research areas, Cunningham said. A second indication is expected to be chosen by the end of 2005, with an IND filed in late 2006.
At the moment, the company has five full-time employees, but it is hoping to add another six, mostly in the regulatory, quality control, and process development areas, later this year, according to Cunningham.
Avocel, founded in early 2003 and named after a bird, the American avocet, was incubated out of B-Bridge International, a Sunnyvale-based biotechnology company “bridging life science ventures in the US and Japan,” according to its website. The firm has an undisclosed amount of funding available from a recent Series A round, raised through a venture fund set up by B-Bridge International, which Cunningham said in an e-mail “will take us to phase I.”