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No Rest for 'Sleeping Beauty'

Dave Largespada, Scott McIvor, Perry Hackett, and Steve Ekker use zebrafish and mouse genes to develop gene transfer technologies

Dave Largespada, Scott McIvor, Perry Hackett, and Steve Ekker use zebrafish and mouse genes to develop gene transfer technologies. Photo: Richard Anderson

A novel gene transfer technology called ‘Sleeping Beauty' was created four years ago with help from Minnesota Sea Grant and an ancient fish gene. It recently won a $2.5 million grant from the Beckman Foundation, attracted $3 million from Techne Corporation to start a new company, and inspired another technology.

Sleeping Beauty Transposon System™ "awakened" in 1997, when Perry Hackett turned a fish gene dormant for 15 million years into a vehicle for integrating foreign genes into human chromosomes. The technique, not to mention the scientists who support it, hasn’t gotten much rest since then. In July of 1999, Hackett and colleagues won a $2.5 million Technology Development Grant from the Arnold and Mabel Beckman Foundation to support further development of the system. The team has used the funding to add a new technology to their repertoire and has set up a company to tackle challenges in genomics.

The four scientists — Hackett, Steve Ekker, David Largaespada, and Scott McIvor — had similar interests to begin with, but the grant has allowed them to integrate their efforts and get a bigger return on their separate research funding.

"The Beckman grant served as a nucleus that drew our four labs together," Hackett explains.

In October 2000 the four scientists set up Discovery Genomics, Inc. (DGI) to broker collaborations with people and companies interested in finding new genes and using the discoveries to design therapies for diseases with a genetic basis. This summer the company got a $3 million boost from Techne Corp. of Minneapolis, bringing its total investment to date to $3.9 million.

Two technologies form the scientific underpinnings of DGI: Sleeping Beauty Transposon System™ and Morphant®. Sleeping Beauty is essentially an enzyme called a transposase that can move a defined segment of DNA into chromosomes. When scientists insert genes into a Sleeping Beauty Transposon, it ferries those genes into the nuclei of cells and then into chromosomes. It originated as an obsolete fish gene that Hackett's lab found, "awakened" — hence the name — and modified as an agent for transferring genes. They performed that work using cultured human HeLa cells and zebrafish, a tiny fish that makes an excellent model for genetic studies. With Beckman funding, the group improved Sleeping Beauty's frequency of gene delivery in cultured cells by 10 times.

Sleeping Beauty has already been put to work in the search for genes. Largaespada, along with scientists in Japan and elsewhere, has used the system to discover genes in mice. The researchers placed Sleeping Beauty in mouse sperm and let it insert into chromosomes at random. The result was a transgenic mouse with a yellow coat instead of its normal black coat. Largaespada published results of this ground-breaking study in the April 2 issue of the Proceedings of the National Academy of Sciences.

Creating the mouse with this technique represents a major step toward the goal of using Sleeping Beauty for gene therapy and finding genes that, when disrupted, can cause cancer in humans. Also working with mice, Hackett and McIvor have achieved long-term expression of genes delivered to lung tissue by the Sleeping Beauty Transposon and the transposase. McIvor and Hackett hope one day to perfect the system to deliver genes to lungs via an inhalant, as well as to liver and blood-forming cells of bone marrow in human patients.

But much remains to be done before the Sleeping Beauty Transposon System™ can be used in people. The second technology, Morphant“, is now on the front burner at DGI.

Morphant® uses DNA analogs that leave chromosomes intact but block the expression of genes by interfering with the translation of messenger RNA. Like the Sleeping Beauty Transposon System™, Morphant® can be used to "knock down" the workings of individual genes. Then, by noting what goes wrong in an organism, the researchers can deduce what the genes do. Ekker's laboratory did much of the groundbreaking work with Morphant® in zebrafish. The system also works in frogs, chickens, sea urchins and fruit flies, he says.

DGI scientists can use Morphant® in two ways: first, by serving customers who want to find the function of a vertebrate gene; and second, to discover genes of interest to DGI scientists themselves. Such genes would be any whose functioning contributes to a health problem and, therefore, creates a potential target for drugs. With a healthy second dose of financing, the company can perform further tests on the workings of both the gene and candidate drugs to bring a new therapy closer to clinical trials.

DGI is well positioned to fulfill the potential of both technologies in its stable. The company holds exclusive licenses from the University of Minnesota to develop technologies related to "knock-downs" in zebrafish produced by Morphant® and to the use of the Sleeping Beauty Transposon System™. The reach of these technologies was extended this summer by an agreement that gives Techne Corp. the rights to develop antibodies and immunoassays for proteins discovered by DGI and an exclusive, royalty-free license to sell such products in the research market.

The four scientists who began DGI maintain close ties with the company and each other. Hackett has taken an indefinite leave from the University to serve as DGI's chief scientific officer. Ekker, Largaespada and McIvor served on the board of directors, resigning when the license agreement with Techne was signed. They remain consultants to the company, which counts them and the University among its stockholders.

"I think there are excellent resources in terms of personnel on the Minnesota scene," says Ekker. "We can compete because we can do things cheaper, better and faster. Our dream is to grow into a longterm therapeutic-based business, doing basic research or providing lead compounds that are relevant to humans."

For more information, visit www.discoverygenomics.net.

Reprinted from Frontiers, a newsletter of the University of Minnesota College of Biological Sciences (winter 2002 issue) and combined with information from a University of Minnesota news release.

By Deane Morrison
June 2002

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