From the death of Jesse Gelsinger in 1999 to the development of cancer by several boys treated for immunodeficiency, gene therapy has been burned repeatedly by problems with viral gene delivery.

The most recent trouble came just last week when Targeted Genetics suspended a Phase I/II trial for its experimental arthritis drug tgAAC94 after the death of a patient. (See BioWorld Today, July 30, 2007.)

Gelsinger, the French boys and last week's patient, whose name has not yet been released, are very different in their details from a medical perspective. But nevertheless, as microorganisms, viral vectors remain, by their very nature, a complex delivery system.

"Though they have been modified" to simplify them as much as possible, "they still have all sorts of issues with respect to inflammation, immunity and unstable integration," Richard Levy, chairman of pediatric cardiology at the Children's Hospital of Philadelphia, told BioWorld Today.

One attempt to get around such problems has been to cut out the viral middleman. The most developed example of this approach is electroporation, which companies such as Inovio Inc. and MaxCyte Inc. are using in clinical programs aimed at cancer, infectious diseases and cardiopulmonary disease.

Another possibility is the use of nanoparticles. Magnetic nanoparticles especially have an obvious way to target them once they are in the body. But for reasons ranging from particle size to chemical characteristics, Levy said, none of the methods that currently are in use in cell culture are suitable for humans, or even animals.

Levy is the senior author of a paper in the August 2007 issue of the FASEB Journal that reports an additional way to deliver genes without resorting to a viral vector: via magnetic nanoparticles.

Levy and his team, who hail from the Children's Hospital of Philadelphia, Boston University School of Medicine and Drexel University School of Biomedical Engineering and Health Sciences, used polylactic acid or PLA, "a well-known biodegradable polymer that is used in many medical applications" already, Levy said.

The scientists complexed the PLA with iron oxide to render it magnetic, and an organic compound called polyethylenimine, or PEI, that enabled the complex to bind free or naked DNA.

Importantly, the PLA-PEI complex also protected the free DNA from attack by nucelases, enzymes present in serum which destroy DNA, and the approach worked even in cell cultures with 50 percent serum in their growth medium, which is roughly the proportion of serum in blood.

Levy said that success is in stark contrast to other attempts at gene delivery in cell culture. He noted that "gene transfer in cell culture often needs to happen under serum-free conditions" to prevent the DNA from being chewed up before it reaches its intracellular destination.

In cell culture, Levy and his team used their particles to deliver adiponectin, which inhibits cell growth, to arterial smooth muscle cells. They found that cells treated with adiponectin grew less than controls; stents eventually can clog up, and so inhibiting cell growth within them could extend their useful life.

Levy said that the universities involved have filed patents on the compound and are "in discussions" with companies about commercialization possibilities. He said the delivery system also may find broader use as a vehicle for delivering drugs, genes or cells to a target organ.

"Right now, there's no reliable way to deliver the cells" to the specific site where they are needed, Levy said. If they pan out, the magnetic nanoparticles could change that. "This system has the potential to be a powerful tool," he added