Gene therapy with long-term effects

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Gene therapy with long-term effects
Gene therapy with long-term effects

Long-term gene therapy

One of the problems that still prevents gene therapy today is the limited period of time that genes introduced into cells are active. With the help of a certain virus, the genes could probably be permanently integrated into the genetic material. An experiment on mice was successful for eight months. Researchers have genetically engineered a virus that could solve one of the big problems in gene therapy, namely how to get therapeutic genes into target cells and keep them working properly. The improved virus, called an adeno-associated virus (AAV), passed its first test by delivering functional genes into mice that had a genetic defect that causes obesity and diabetes. The animals remained he althy with the gene for up to eight months (Proceedings of the National Academy of Sciences, Vol. 94, pp. 13921-13926). Although this approach is not suitable for the treatment of obesity in humans, the virus could probably be used as a gene transport agent in the therapy of other diseases.

The new results are a significant advance on previous work with adenoviruses. It is true that this type of virus can transport foreign genes into mammalian cells; however, cells that have ingested an adenovirus are killed by the immune system within three to four weeks. Adeno-associated viruses-a widespread class of viruses always found among adenoviruses but which do not cause disease in humans-do not elicit this powerful immune system response. "Different groups are working on delivering genes using this system," says Varavani Dwarki, a gene therapy researcher at Chiron in Emmeryville, California."But the question remained: How long can you keep the genes functional?"

Dwarki and Jaime Escobedo improved the AAV's ability to insert genes into chromosomes. They placed a promoter region from cytomegalovirus in front of the gene. These promoters are known to be active in the target tissue for the intended gene therapy, the muscle cells. To test the new vector, the researchers added the gene for leptin. Leptin acts as a satiety signal and interacts with cells that are important for insulin production. Mice without the gene overeat, weigh three to four times their he althy counterparts, and develop symptoms similar to a form of human diabetes that is linked to obesity.

Just eleven weeks after a single injection of gene therapy, ten young mice lacking the leptin gene regained the weight, insulin, glucose and leptin levels of comparable normal mice. In addition, the mice ate less, were more active, and had fewer diabetic symptoms than leptin-deficient mice that had not received therapy. Dwarki noted that the weight of the treated mice was maintained for more than 8 months. "The [untreated] mice look like big blobs of fat while the others are skinny and walking around," he says.

According to molecular geneticist Rudolph Leibel of Columbia University in New York City, the study clearly shows the utility of the adeno-associated virus for long-term gene transfer. However, Leibel points out that this finding will not help most obese people. Since most cases of human obesity and diabetes are not caused by a single gene, there is only "a small chance of a cure with a single injection."

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