Jumping Genes Could Help Make Gene Therapy Safer

To move a gene from one point to another, investigators have two established options: a virus, which can effectively transport genes of interest into cells, and a plasmid, a modified loop of DNA that can do the same thing, although typically only on a short-term basis.

The problem is that viruses can be infectious, and some types of viruses occasionally settle in a target genome near an ontogeny (the site of the development of an organism from the moment the egg is fertilized up till adulthood), and thus increase the risk of cancer. Plasmids do not carry that risk, but they are not nearly as effective at reproducing in cells, which is important when the plan is to integrate an introduced gene into the targeted cells of the organism or patient.

Now, however, the advent of new nonviral gene delivery systems using transposons, or "jumping genes,” provides a safer alternative to viruses and more efficient delivery than plasmids, according to researchers from the University of Wisconsin- (UW)-Madison (USA).

In an article in the September 2007 of the journal Applied Biosafety, UW-Madison molecular biologist and associate biological safety officer Dr. Margy Lambert described the gene delivery potential of transposons, stretches of DNA capable of jumping from one DNA molecule to another. "Almost any application where you use viral vectors, you could use this technique,” explained Dr. Lambert. "You can do a lot with it, and it is safer. Problems with viral vectors are extremely rare, but the consequences can be severe.”

Gene therapy, according to Dr. Lambert, is one area where the new technology could really establish itself. Currently, there are an estimated 140 gene therapy trials under way in the United States. Most are geared at treating fatal conditions such as cancer. Many use the less-efficient plasmids as expression vectors, but some utilize viruses, and no gene therapy treatment has been deemed safe or effective enough to merit Food and Drug Administration (FDA) approval as a routine therapy.

Moreover, occasionally unanticipated outcomes that contradict the safety of current gene therapy strategies manifest themselves in tragedy. In July 2007, for example, a 36-year-old woman from the United States died after experimental gene therapy treatment in which a modified virus was injected into her knee to treat rheumatoid arthritis. The viruses used were engineered to suppress the immune system only in the knee. In the case of rheumatoid arthritis, the immune system is out of control and is responsible for the painful inflammation characteristic of the condition. The FDA has placed the trial on hold while the cause of death is investigated.

Transposons, or jumping genes, argued Dr. Lambert, are a potentially safer application to use. "You lose the infectivity component and you minimize the insertional mutagenesis risk.”

Techniques for targeting transposon vectors to areas of the genome devoid of cancer genes are being modified. In the meantime, a major advantage over simple plasmids is that jumping gene technology is more effective at achieving stable expression of genes introduced into animal cells.

To control jumping genes, researchers utilize an enzyme to move a desired DNA sequence from one DNA molecule to another inside a cell. The enzyme can then be inactivated to stop genes from jumping. Dr. Lambert acknowledged there are both technical and safety issues to be worked out in the development of transposon vectors before they could be tried in human therapy. But the use of such new vectors "offers a great opportunity to maximize the advantages and minimize the drawbacks of existing delivery systems.”


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