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New Drug Delivery Approaches Critical to SiRNA Comeback

By Nuala Moran
Staff Writer

VANCOUVER, British Columbia – After the initial hype and some eye-watering investments, big pharma has abandoned the field of silent interfering RNA (siRNA) in the face of seemingly insuperable problems in getting those constructs to their targets.

But now academic scientists say they are beginning to overcome the challenges of delivering siRNA that have so far deterred the industry. "The future is not all gloom: In my view, academe is providing a better opportunity to solve the delivery problems and usher in an era of genomic medicine," Bill Beck, of the University of Illinois, Chicago, said at the American Association for the Advancement of Science meeting over the weekend.

SiRNA offers huge potential for the development of targeted therapeutics for cancer and other diseases. However, those readily synthesized drugs need to be delivered into the cytoplasm of specific cells if they are to exert their modulating effect. To date, that has been difficult to achieve.

There are several reasons it is worth working to overcome the difficulties of delivering siRNA, Anil Sood, of the University of Texas MD Anderson Cancer Center, told delegates. For a start, many important targets are not druggable with small molecules, or if they can be addressed, there are unacceptable side effects. SiRNA, on the other hand, offers the possibility of completely shutting off the gene of interest.

Sood said he does not believe viral vectors represent a good means of delivery and, instead, is working to stabilize siRNA with chemical linkers. The key challenge is how to get inside tumor cells.

In the initial hype, there was some published research claiming it might be possible to deliver naked siRNA, but Sood said he is skeptical. He has been working with siRNA encapsulated in liposomes and has filed for an FDA investigational new drug application to conduct a trial of liposome-delivered EphA2/eck, a protein kinase that is a regulator of angiogenesis.

However, devising the means to deliver siRNA to the cytoplasm of target cells solves only half the problem. Sustained gene silencing calls for repeated dosing, and Sood also is working on a "multistage" delivery vehicle using liposomes to deliver siRNA particles that are coated in a silicon material that progressively biodegrades over time.

"To date, we can get gene silencing for up to 20 days," Sood said. The potential of that is highlighted by the fact that, as of now, 24 targets have emerged in angiogenesis that offer the prospect of interrupting the formation of tumor vasculature.

Sood has demonstrated it is possible to deliver siRNA to tumor endothelial cells. "We have shown we can shut down a target of interest in the stroma and in the tumor," he said.

"Despite the barriers – and large pharma pulling out –we do think there are opportunities. We think it is clinically feasible to deliver siRNA to tumors," Sood added.

Similarly, Patrick Stayton, of the Center for the Intracellular Delivery of Biologics at the University of Washington, described work to develop polymer carriers for siRNA. Taking viral pathogens as role models, Stayton became interested in one of the conserved pathways by which the flu virus invades cells. That involves the virus prompting a fall in pH, which in turn activates membrane destabilizing mechanisms, enabling the flu virus to steal in the cytoplasm.

In parallel to his academic post, Stayton is a consultant to the siRNA delivery specialist PhaseRx, of Seattle, which is trying to mimic the pH-induced membrane destabilization employed by the vaccine by using a synthetic polymer carrier. Stayton said the "dream design goal" is to come up with a polymer that "actively aids" intracellular delivery.

In effect, such a carrier would be viewed by the FDA as an integral part of the drug, Stayton said. "The polymer provides pharmacokinetic enhancements, and the carrier and the drug is one molecular entity but [is] multi-functional."

Recent advances in polymer chemistry make it easier to synthesize complex polymers to which it is possible to conjugate both targeting agents and biologic drugs. Significantly, such entities are able to bypass lysosomal trafficking.

"We have seen good endosomal release of a number of biologics," Sood said.

While there are good reasons to develop synthetic polymer siRNA delivery systems to replace viral vectors, such systems are not yet ready for clinical application.

"We aren't there yet; we can't do as well as viruses [in delivering siRNA], so it is still an open question what the clinical significance is going to be," Sood added.