Frank Giordano's patients need new blood vessels: some have blocked arteries around their hearts, and others have poor circulation in their limbs. In a few cases, the Yale University cardiologist and molecular biologist has coaxed new vessels to grow using conventional gene therapy, injecting patients with genes that encode a natural protein called vascular endothelial growth factor. But he's most excited about a new treatment that, instead of relying on imported genes, stimulates the patients' own genes to work harder.

For now, Giordano's patients are strictly of the furry rodent variety, but the substances he's testing-engineered transcription factors that act directly on DNA to stimulate or block protein production-could herald a new approach to treating human disease. Sangamo BioSciences in Richmond, CA, designs transcription factors that bind uniquely to DNA sequences near specific medically relevant genes and turn protein production up or down at the source. "It's like a rheostat for any protein you want," says Casey Case, Sangamo's vice president of research.

Case says the technique has distinct advantages over existing gene therapy methods. In gene therapy-still an experimental treatment itself-genes are injected into a patient and provide instructions for making a single version of a protein; but native genes often code for several versions of a protein, each of which can play an important biological role. Because an engineered transcription factor turns on the body's own copy of a gene, all of these versions of a protein are made. Giordano says, for example, that mice producing all the variants of the blood vessel growth factor seem to have "more robust" vessels. And because Sangamo can engineer transcription factors for any genes-including those involved in cancer, diabetes, heart disease or nerve repair-"the sky's the limit" for other therapeutic applications, he says.

Paul Robbins, a gene therapist at the University of Pittsburgh, speculates that the approach could also be used in treatments for cancer and inflammation-and he predicts that with further research, the technique could offer even more control over gene expression. "This technology is at its very beginning," Robbins says.