Gene Therapy That Lasts

Researchers have genetically engineered a virus that might overcome one of the big problems facing gene therapy: how to ferry therapeutic genes into target cells and keep them functioning. The improved virus, called an adeno-associated virus (AAV), passed its first test by delivering working genes into mice with a genetic defect that causes obesity and diabetes. The animals stayed healthy for up to 8 months. While experts say the advance--reported in today's Proceedings of the National Academy of Sciences--won't help human obesity, the virus may be able to carry genes to treat other diseases.

The new results are a marked improvement over earlier work with a companion virus called an adenovirus. Adenoviruses can deliver foreign genes into mammalian cells, but within 3 to 4 weeks the immune system kills cells that have taken up the virus. AAVs, a class of common viruses that are always found with adenoviruses but produce no disease in humans, do not trigger this strong immune response. "Several groups are working on delivering genes using this system," says Varavani Dwarki, a gene therapy researcher at Chiron Corp. in Emeryville, California. "But the question had remained: How long can you get the gene expression to last?"

Dwarki and Jaime Escobedo improved the AAV's ability to insert genes into chromosomes by adding a gene promoter region from cytomegalovirus, known to be active in the target for their gene therapy, muscle cells. To test the new vector, the team added the gene for leptin, which acts as a satiety signal and interacts with cells important in insulin production. Mice without the leptin gene, called ob/ob, overeat, weigh in at three to four times normal, and develop symptoms similar to the obesity-related diabetes seen in humans.

Just 11 weeks after getting a single shot of the gene therapy, 10 young mice lacking the ob/ob gene reached weight, insulin, glucose, and leptin levels comparable to normal mice. The mice also ate less, were more active, and had milder diabetes symptoms than leptin-deficient mice who received no therapy. Dwarki notes that the weight has stayed off the treated mice for more than 8 months. "The [nontreated] mice look like huge blobs, while the others are thin and running around," Dwarki says.

The study clearly shows the utility of the adeno-associated virus in long-lasting gene transfer, says molecular geneticist Rudolph Leibel, an obesity researcher at Columbia University in New York City. Leibel points out, however, that the finding won't help most obese people. With no single gene believed to be responsible for most cases of obesity or diabetes in humans, there's "little likelihood of a cure with a single injection."