Challenges

Great Promise, Greater Challenges ene therapy, the treatment of disease by introducing new genetic information into the body, is a procedure with tremendous promise, but with disappointing results thus far. In large part, this lack of success results from a number of basic biological and technological problems that have not yet been solved. Advances are being made, however, that suggest gene therapy will ultimately be a powerful approach to treating many conditions such as coronary heart disease, cancer, and infectious diseases. Successful treatment depends on the ability ofa gene to produce a key protein when and where it is needed.

Gene therapy is rooted in the advances that have been made in microbial genetics, molecular biology, and virology. The idea that it might be possible to introduce genes into mammalian cells and correct life threatening conditions was first suggested by a number of scientists who worked with microbes and studied gene transfer in bacteria. These included Joshua Lederberg and Edward Tatum, co-discoverers of conjugation in E. coli. Lederberg also discovered transduction by a bacterial virus. It was a small step for these investigators to suggest the possibility of gene transfer into mammalian cells by an animal virus.

Viruses are the most popular vectors for introducing genes into cells. They have the ability to be taken up by specific tissues

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and then induce the cells' machinery to synthesize protein from the introduced genes. The desired genes are merely cloned into the viral genome and these will be introduced into all cells the virus infects.

The major challenge of gene therapy is to design a viral vector that can deliver and express genes in mammalian cells with great efficiency and absolute safety. A long-term goal is to deliver useful genes to the right spot and have them turn on and off at will. Considerable progress is being made to achieve these goals.

The two most common viral vectors currently being used are retroviruses, which include the HIV virus, and adenoviruses, a common cause of colds. The former results in integration of nucleic acid into the host cells, whereas the latter leads only to expression of the viral genes for a short period of time while the virus replicates, referred to as transient expression.

This latter approach is now receiving most attention, since the treatment of certain conditions may only require a brief synthesis of protein to activate the genes of the host cells, which could continue the process. For example, it may be possible to "kickstart" the immune response against tumor cells by provoking specific killer T cells to attack tumor cells. Also, encouraging experiments suggest that it might be possible to stimulate the growth of new blood vessels around blocked arteries by introducing genes for fibroblast growth factor using adenovirus vectors. One can envision that bone growth, skin growth, and hair growth might also be promoted through gene therapy.

The promise of gene therapy has been on a roller coaster. First there was great hope of curing many diseases caused by defective genes, such as cystic fibrosis and hemophilia. However, the issues of safety, resulting from the death of a young patient, and the realization that the problems are much more difficult to solve than originally envisioned, have now pushed those hopes for curing genetic diseases into the distant future. Expectations are now more limited and realistic. Nevertheless, the advances that have been made recently in basic studies of virology, immunology, and gene expression in the laboratory should go a long way toward transforming a great promise into reality.

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