10 September 2007; | doi:10.1038/news070910-1

Improved polymer shuttles genes into cells

Biodegradable chemical could one day provide nonviral gene therapy.

Heidi Ledford

The new technique works in mice tumours. Getty

Scientists have created a biodegradable polymer that can shuttle DNA into cells, raising the possibility that the compound may one day provide a safer way of performing gene therapy.

There have been more than 1,000 trials of gene therapy, a pioneering way of fixing genetic defects by introducing new genetic material straight into a person's DNA; most of these have been early stages of clinical trials, to test for safety.

Most of the trials rely on viruses to escort therapeutic fragments of DNA through the gauntlet of cell membranes and myriad chemical landscapes of the body, to insert it into a person's DNA. Safety concerns about these viruses, including their potential to cause cancer, have made nonviral approaches an attractive alternative.

Researchers have tried several methods, from wrapping genes in positively charged lipids to injecting pure, 'naked' DNA. None has achieved the efficiency of a virus. "It's a hard thing to do to get DNA, which is this huge, floppy, negatively charged molecule, from outside the body, through the body, and then into the cell," says bioengineer Daniel Anderson of the Massachusetts Institute of Technology in Cambridge. "There are a lot of barriers."

Now Anderson and his team have succeeded in using a polymer, known as a poly(beta-amino ester), to successfully insert a gene into mouse ovarian tumours, a process known as 'transfection'. In cell culture, the new compound was able to transfect more than twice as many cells as the leading nonviral reagent available.

The resulting level of gene expression rivalled that achieved by adenovirus, a commonly used gene-therapy vector.

"There really hasn't been any nonviral system that can transfect human cells this well," says Anderson. In this case, the inserted genetic information simply made the mouse tumours express a fluorescent protein. The same technique could, in theory, be used to deliver more useful strings of DNA. That has yet to be trialled in live animals.

Success in the end

The work follows on from earlier studies using positively charged polymers that clump together with nucleic acid to form nanoparticles. Previously, some of these polymers have been made to deliver their DNA or RNA cargo to the inside of a cell. But they often work only for short periods of time, and have to be used in concentrations that were deemed too high for clinical use in humans.

Anderson and his co-workers took a number of poly(beta-amino ester) polymer backbones and gradually tweaked them, piece by piece, looking to improve their efficacy. They created a library of variants by chemically modifying the ends of the polymer, and looked for molecules with improved transfection efficiency.

The successful polymer had had both ends capped with a molecule called primary diamine, increasing its ability to deliver DNA - possibly by increasing the overall positive charge of the molecule. The results are published in Advanced Materials.

Anderson says that his team will continue the work in animals, with an eye to moving to clinical trials in humans.

Transient expression

Although the results in cell culture are promising, it is still unclear how well these polymers will function in live animals, cautions biochemist Francis Szoka of the University of San Francisco in California. "They still have a long way to go to show that it will be useful for in vivo gene transfer," he says.

Specifically, Szoka is concerned that the researchers only evaluated the activity of the introduced genes in mice up to six hours after the polymer - DNA combo was injected. Given that genes introduced by previous-generation polymers had functioned only transiently, six hours of gene expression is not enough to convince him that the same won't be true of Anderson's modified poly(beta-amino ester), he says.

And, although Anderson and his colleagues directly compared their polymer with adenovirus in tissue culture, they did not perform a direct comparison in live mice. Previous claims of success in cell culture have not fared as well in animals. "So far nothing has been able to translate into animals with good, high rates of transfection," says Szoka.

Reference : Green, J.J., et al. Adv. Mater. doi: 10.1002/adma.200700371 (2007).

Photo NOAA/AP

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Dimanche, Félix a balayé Aruba, Curaçao et Bonaire avec de la pluie et du vent, provoquant ça et là des coupures de courant et obligeant des milliers de touristes à trouver refuge dans les hôtels. Mais les habitants ont exprimé leur soulagement car l'ouragan a fait beaucoup moins de dégâts que ce que l'on craignait...

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Source et illustration: NASA/JPL/Space Science Institute

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