Gene Therapy Success in the Flesh

What may sound like an ad for a futuristic tanning salon is actually a triumph of gene therapy research: A tweaked gene turns the skin cells of albino mice a dark color that lasts for weeks. The result, reported in this month's Nature Biotechnology, suggests that researchers may be able to mend flawed genes with surgical precision.

The main strategy for permanently compensating for mutated genes has been to deliver a working copy of the gene via a disarmed retrovirus. Unfortunately, the gene doesn't always work, and viral carriers insert the new DNA randomly into the genome, potentially crippling other genes. It's also like getting a new roof when just a lone shingle leaks, because many diseases are caused by just a single mutated DNA base in a gene.

One promising alternative is a "chimera" molecule, forged of RNA and DNA, that can be slipped into cells inside fatlike spheres called liposomes. The chimeras bind to the cell's DNA alongside the mutated base and fool repair enzymes into fixing it. Two years ago, researchers reported that chimeras could mend the hemoglobin gene that leads to sickle cell anemia (Science, 6 September 1996, p. 1386). While exciting, the result was greeted with skepticism, says co-author Kyonggeun Yoon of Thomas Jefferson University in Philadelphia. Some scientists questioned the team's evidence for the mended gene, partly because they hadn't shown that it was inherited by subsequent generations of cells.

Now Yoon and colleague Vitali Alexeev say they have clear proof that their technique repairs the cells' own DNA. They fashioned a chimera to fix cultured mouse skin cells that were albino because of a single mutation in an enzyme for making melain. After a few days, the chimeras had darkened 0.01% to 15% of albino cells. The team showed they could detect both repaired DNA and the corrected enzyme in the pigmented cells, and that the change persisted in cloned copies of the cells for more than 3 months. "It's gene surgery," says University of Miami gene therapist Richard Bartlett, who thinks the doubters will now be convinced.