United Press International - Sunday, 24 December 2000
Gargi Talukder, UPI Science News

The aim of gene therapy is to correct genetic disorders by inserting new, functional versions of genes that compensate for the inherited defects. Because it uses the body's own machinery to produce a cure, the strategy should in theory have limited side effects with maximal benefit.

As a concept, gene therapy isn't new -- it's been bandied about for two decades or more -- but it is far behind schedule in its promise to revolutionize treatment of disease. Simply put, the body is awfully good at repelling intruders, no matter how beneficial their intent.

Now recent studies suggest HIV, herpes and other viruses, with their notorious efficiency in infecting human cells, may become excellent gene "ferries" for correcting illnesses instead of causing them.

Traditionally, a major stumbling block to successful gene therapy is a stable method of transferring genes safely into human cells. It's been difficult to find such a method, called a vector, which can convey the large quantity of DNA necessary to correct genetic deficiencies.

A second problem with many vectors is that they are not very efficient, meaning that for any given amount of vector used, very few of the molecules actually make it into the cells the researchers are trying to target.

Recently, however, researchers at Harvard University Medical School and the Wellcome Trust Centre for Human Genetics in Oxford successfully used a herpes virus system to correct a genetic defect in a line of human lung cells.

Richard Wade Martins and colleagues have targeted an enzyme, expressed in virtually all cells, called HPRT for hypoxanthine phosphoribosyltransferase. Mutations in DNA coding for HPRT result in debilitating illnesses such as gouty arthritis and Lesch-Nyhan syndrome, an inherited disease among males characterized by mental retardation, aggressiveness and self-mutilation starting at about age two.

The scientists began with the Epstein-Barr virus, a human herpes virus abbreviated EBV, as their vector. They then removed its "bad" genetic information, leaving only the parts that make the virus so effective at penetrating foreign cells. The strategy also created space inside the virus to carry the genetic material necessary to correct the HPRT deficiency.

One problem that remains with many viral vectors, however, is that they are not able to infect non-dividing cells. That's where HIV can help, according to researchers at the Salk Institute, La Jolla, Calif., the University of California, Los Angeles, and other organizations.

Most of the body's cells reproduce by doubling all of their genetic material and then dividing into two identical "daughter" cells. Many gene therapy vectors are only able to infect cells that are in this process of division. But because not all the cells in a particular tissue are dividing at the same time, most vectors very inefficient at transferring genes to the target cells.

In addition, some cells in the body, such as certain brain cells and cells in the retina, no longer divide once we reach adulthood. Gene therapy methods to cure diseases affecting these cells would require a vector that can efficiently infect a non-dividing cell.

One virus that is effective at targeting non-dividing cells is HIV. Current protocols for developing HIV-based gene therapy vectors usually package them without the accessory genes that cause HIV replication in humans, thus increasing the safety of these vectors without affecting the efficiency of vector production.

For example, researchers at the Salk Institute have shown that HIV-based vectors can be directly injected into the rat and mouse retina, and that the transferred genes are stable in the retina for at least six months. Researchers at UCLA have further shown that HIV-based vectors can efficiently transfect a line of human cells.

These results could eventually lead to gene therapy treatments for degenerative eye disorders in humans, such as retinitis pigmentosa, which is caused by mutations in a retinal protein and can eventually lead to blindness. At the moment, there is no effective treatment for this illness.

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