New and Improved Package for Gene Therapy

Viruses are gene therapy's answer to the Trojan Horse. With their wily knack for invading the cells of other organisms, viruses should be an ideal courier of beneficial genes into diseased cells. But there is no single virus with all the right powers. Now researchers have created a hybrid that might do the job.

The aim of gene therapy is to repair damaged DNA, fix a harmful gene, or replace a missing gene--all by outfitting a virus with genetic material that then gets incorporated into a cell's own DNA. It's not as simple as it sounds, though. The viral vector must accomplish two feats: gain entry into the host cell and then embed itself--and the therapeutic gene--into the cell's DNA. The stumbling block is that each virus in the current lineup can only master one of these tricks.

To create a virus that can both enter target cells and stay there, dentist Bruce Baum of the National Institute of Dental and Craniofacial Research in Bethesda, Maryland, and colleagues started with an adenovirus, which causes the common cold. Stripped of its disease-causing genes, the virus doesn't provoke an immune response and is safe to use. It's also easy to mass-produce in the lab. On the downside, however, an adenovirus can't force its way into the nuclei of mature, nondividing cells--the usual target of gene therapy.

The researchers then spliced genetic elements from a retrovirus into the adenovirus. Retroviruses don't invade cells efficiently and they're difficult to reproduce in the lab. But retroviruses are able to pierce the nuclear membrane of mature cells and weave themselves into the host genome. To check for success, the researchers added a gene for luciferase, a glowing enzyme derived from fireflies, and injected the hybrid into lines of human and rat cells. The hybrid integrated luciferase into 15% of the cells, a much higher rate than adenovirus alone achieves, the team reports in the February Nature Biotechnology.

Although the hybrid virus didn't contain any therapeutic genes, it's the most promising debut to date, says oncologist Charles Link of the Iowa Methodist Medical Center in Des Moines. The advantage is that the new virus uses less retroviral material than previous attempts, says Link, thus it has more room for beneficial genes. "Baum and colleagues may have stumbled upon a new strategy with implications for many genetic disorders," says Link.