Promising non-viral alternative for gene therapy involves jumping gene from a moth

University of Hawaiʻi at Mānoa
Posted: Oct 5, 2006

HONOLULU — A jumping gene first identified in a cabbage-eating moth may one day provide a safer, target-specific alternative to viruses for gene therapy, researchers say.

Dr. Stefan Moisyadi, a University of Hawaiʻi molecular biologist, collaborated with scientists from Switzerland and the United States on the study involving the jumping gene, or transposon, known as piggyBac. Their research was recently published in the online Proceedings of the National Academy of Sciences Early Edition.

Viruses, which most people try to avoid at all costs, are wonderfully efficient at getting into the cells of their host organisms and inserting themselves into their host‘s DNA. Researchers have been trying for more than 20 years to harness this power in order to deliver beneficial gene therapies to patients. However, viruses are not easily controlled and run the risk of triggering an immune reaction or activating cancer-causing genes. In fact, in one study, three patients developed leukemia after the virus inserted itself upstream of a cancer-causing gene, and in another study, a patient died because of an immune response to an adenovirus.

"A non-viral gene therapy method that can insert therapeutic genes effectively and efficiently into mammalian cells is critically needed in the biomedical field," says Moisyadi.

Moisyadi and collaborators discovered that the most efficient non-viral method for inserting therapeutic genes into mammalian cells depends largely on the actions of a transposon. Previously used in insect transgenesis, transposons have recently been applied to mammalian genetic modifications.

However, low efficiencies and random insertions into genomic DNA have limited the usefulness of transposons. Moisyadi suggests that the jumping gene technology could prove to be what the gene therapy field was seeking.

Moisyadi and Dr. Joseph Kaminski, a radiation oncologist at the Medical College of Georgia, sought to discover which transposons insert DNA most efficiently into human cells and which have the potential to deliver transgenes to safe regions of the genome.

"Typically, viruses and transposons will integrate anywhere along the genome," said Kaminski. "If they integrate just anywhere, it can obviously cause harm. If we can target the integration, be able to insert the gene at a safe spot in the genome, that would be beneficial."

"We can do it in insects," says Moisyadi. "I think it‘s a short step to take it to a targeting mechanism we can use in mammals."

Moisyadi and Kaminski explain that, as an analogy, a person would not want to park their car on a railroad track. Therefore, the location of the transgene after insertion is just as important as the ability to insert it in the first place.

Until recently, a transposon popularly known as Sleeping Beauty was thought to be the most efficient in inserting genes into mammalian systems. However, a drawback to Sleeping Beauty is its inability to be modified to overcome concerns about placing therapeutic genes safely within the genome. Moisyadi and Kaminski compared a number of transposons and found that piggyBac is much more efficient at inserting transgenes into the genome of several human lines. It is also amenable to molecular alteration so that it can potentially insert a therapeutic gene into a safe area of the genome. In fact, the piggyBac transposase enzyme that performs the insertion of the transposon into DNA can now be modified to attempt placing the transgenes into pre-designated regions of the genome — targeted insertion.

Although piggyBac is not as efficient as the virus at integrating into DNA, "we could potentially make a hyperactive version of piggyBac, like they did for Sleeping Beauty, which might be as good or better than retroviruses," Kaminski said. "I think we‘ll do it or somebody will. I think it‘s a safer method."

"At the moment, unless something new comes out, it‘s the only way to go because viruses have been killing people," says Moisyadi, who has avoided viruses in his transgenesis studies.

"One of our next goals is to use transposons to deliver a radio-protective gene, called manganese superoxide dismutase, to potentially protect normal tissue from radiation damage," said Kaminski.

In cancer, he suspects gene therapy will focus on this type of modification of normal tissue for protective purposes as well as manipulating the immune response. However, it has broad applications for correcting single gene disorders, such as hemophilia, sickle cell disease and muscular dystrophy.

Other collaborators involved in this study include Dr. Sareina Chiung-Yuan Wu, lead author, and Dr. Yaa-Jyuhn James Meir of the Medical College of Georgia, and researchers from Texas A&M University‘s Department of Entomology; U.S. Department of Agriculture Center for Medical, Agricultural and Veterinary Entomology; and the University of Zurich‘s Institute of Laboratory Animal Sciences.


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