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Sleeping Beauty, back in business

After 13 million years of slumber, the Sleeping Beauty transposon wakes up to a bright future in cancer immunotherapy.
Perry Hackett\

Immunotherapy is a bit of buzzword these days, but is it actually possible to fight off cancer by supercharging the immune systems of patients? A recent $100-million licensing deal for genetic technology developed at the U of M seems to indicate that the answer could be yes.

It all started in the midst of economic travail for northern Minnesota’s sport-fishing industry. Whereas bigger fish were ending up in the pan, slower growing fish were being caught and released, imposing a heavy selective pressure. “It was evolution right in front of our eyes,” says Perry Hackett, professor of Genetics, Cell Biology and Development, and a member of the Masonic Cancer Center's Genetic Mechanisms of Cancer Program. Hackett wanted to reintroduce genes for faster growth into game fish populations. “We decided to take a whole new strategy and go with transposons as vectors.”

Transposons are DNA sequences that “jump” from one location in a genome to another. Theoretically, desirable genes could be inserted into a transposon and delivered directly to their target. Most modern transposons, though, have lost their jumping ability due to millennia of acquired mutations.

Not to be deterred, Hackett’s international team hit the bench and pieced together DNA sequences from ancient fossils and modern fish to “kiss” the Sleeping Beauty (SB) transposon back to life. Yet when they tested the transposon on living cells, they found its activity was far better supported in human cancer cells than in the fish it had been intended for.

This serendipitous surprise launched SB on a whole new trajectory with a deal between two pharmaceuticals and the M.D. Anderson Cancer Center in Texas, where new SB-based drugs are being tested.

“One direct way you have impact is if industry can take the ball and run it over the goal line,” says Hackett, who has co-founded two biotech startups. This deal is exciting for exactly that reason — it could have major impact.

Unlike viruses, the traditional vector for delivering therapeutic genes, transposons lack complicated protein elements. They are simple DNA strands that can be easily synthesized, purified and stored. Creating enough virus for one or two patients takes six months, but huge quantities of SB can be made in a week. Better yet, the immune system launches no dangerous attacks against DNA like it does against most viruses. Perhaps best of all, preliminary evidence suggests that SB therapies might only have to be administered once or twice in an entire lifetime.

“What M.D. Anderson did was to take all of their know how and translate SB from the bench to the bedside,” says Hackett. It’s an exciting victory for genome engineering technology — one that promises a sigh of relief from sufferers of many genetic diseases.

Masonic Cancer Center, University of Minnesota is part of the University's Academic Health Center. It is designated by the National Cancer Institute as a Comprehensive Cancer Center.  – Colleen Smith

January, 2015