New Gene Therapy Technique Results In 60 Percent Tumor Regression Rate

March 20, 1998

ATHENS, Ohio -- Scientists at Ohio University and a California-based biotechnology company have used a nonviral gene expression system invented here several years ago to eliminate human cancer cells in animals, achieving a 60 percent tumor regression rate without the potential dangers associated with conventional viral gene therapy techniques.

Scientists in the university's Edison Biotechnology Institute are collaborating on the project with Progenitor Inc., which has licensed the T7 gene expression system used in the studies. If further tests of the method prove as successful as these early studies, scientists could begin human trials in the next year or two.

For the study, scientists used a gene therapy protocol widely used in research of human cancer in animal models: They stimulated cellular expression of a herpes simplex virus-thymidine kinase (HSV-TK) gene in tumors, then treated the tumor-bearing animals with the drug ganciclovir. In their studies, 30 percent of the tumors were permanently eliminated.

While similar tests of the HSV-TK/ganciclovir protocol have suggested it effectively kills cancer cells, previous studies used viral vectors to deliver the HSV-TK gene to the cells. Since viral vectors aren't transient, it's possible the viruses could infect healthy cells and cause mutations that could become part of the genome. For this and other reasons, scientists have been looking for a nonviral delivery system to use with gene therapy treatments, says Xiao Chen, lead author of the study and an assistant professor of clinical research at Ohio University's Edison Biotechnology Institute and College of Osteopathic Medicine.

The work was published in the latest issue of the journal Human Gene Therapy, published March 20.

"Viral gene therapy vectors are very efficient in delivery of therapeutic genes to certain targeted cells, but there are safety concerns associated with the viral vectors," Chen says. "Results of our studies of the T7 system suggest that it may be used as an alternative to viral vectors for cancer therapy and other transient gene therapies, or biological applications that require temporary but rapid and efficient gene expression."

Ohio University scientists have long suspected that the T7 gene expression system would produce similar tumor reduction rates to viral vectors and these new studies confirm that, says Thomas Wagner, distinguished professor of molecular and cellular biology at Ohio University and principle investigator on the T7 project at the Edison Biotechnology Institute. The benefit to using T7 for gene therapy, Wagner says, is that the genes expressed using this method are transient and do not become part of the cell's chromosomes. Also, T7 allows genes to be expressed outside the nucleus of a cell, which means it can be used on cells that aren't dividing.

"We think this is why we had such positive results of total and permanent regression of the tumors we studied," Wagner says. "While most cancer cells are dividing, oncologists tell us that in the core of many tumors there are large populations of nondividing cells. These cells may be the source of the recurrence of cancer."

But in their studies, the T7 system allowed for expression of the HSV-TK gene in all cells in the tumor, even those that weren't dividing. The high level of gene expression, another benefit to the T7 system, is due to its design, Wagner says. While other gene therapy techniques use only DNA genetic material, the T7 method uses DNA prebound with T7 RNA polymerase -- a protein that causes the gene to begin producing RNA immediately, an important step in protein synthesis within a cell.

The T7 technology, which was patented by Ohio University in January 1997, is also being studied at Progenitor, where scientists are conducting animal studies with T7 to measure its effectiveness on brain and skin cancers. While their studies have been successful, scientists at Progenitor are trying to improve the efficiency of the technology and improve the product form for commercial purposes, says Ralph Snodgrass, co-author of the study and vice president of research and chief scientific officer at Progenitor.

The researchers say clinical trials are likely sometime in the future, but before trials can begin, scientists want to enhance the expression system to allow for a higher rate of tumor regression. In their studies, scientists at Ohio University and Progenitor have noted that in some mice, tumor regression was partial and in others it was complete. Snodgrass believes the problem may lie with the way the DNA is delivered to the tumor cells.

"In some tumors, you might only need gene expression in 10 percent of the cells to be effective. But in other tumors, you might need expression in 25 percent of the cells," he says. "Some cells take up the DNA very easily but others may need some help."

Scientists are investigating the possibility of using different lipids or other molecules to improve the delivery efficiency and consistency of the T7 system.

But when clinical trials do begin, the system might work like this: Physicians would do a CT scan of the tumor, identifying its exact location. An automated injection system could be used to inject the T7 protein package into every segment of the tumor. Chen and Wagner have found that a series of injections increases tumor regression, so it's likely the patient would require several rounds of this therapy.

Once the HSV-TK gene began to express in the cell, the patient would receive intravenous doses of ganciclovir. Tumor regression should be evident in a matter of days, Snodgrass says. Unlike chemotherapy, which isn't selective in the cells it kills, this genetic therapy would wipe out only the diseased cells.

While the potential for T7 in cancer gene therapy treatments is the primary application for T7 at Progenitor, Snodgrass says he also is investigating the use of T7 to prevent a common postoperative problem for heart patients who undergo angioplasty. The system could be used to deliver a molecule that would prevent blood vessels from closing, which happens frequently following angioplasty.

"The fact that T7 is a nonviral system that doesn't integrate with the genome means that we don't have the safety concerns we have with viral vectors," Snodgrass says. "That and the fact that you don't need dividing cells for the system to work makes this technique very appealing to us."

The Edison Biotechnology Institute is a Center of Excellence within the Edison BioTechnology Center headquartered in Cleveland and is funded in part by the Ohio Department of Development's Thomas Edison Program, a project designed to promote economic development in Ohio.

Other study authors include Yunsheng Li, Keyong Xiong, Simona Aizicovici, Yuefeng Xie and Qin Zhu, all from the university's Edison Biotechnology Institute, and Franck Sturtz, Janine Shulok and Doros Platika from Progenitor.

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Ohio University: David Wight, (740) 593-4713;, or
Kelli Whitlock, (740) 593-0383;
Progenitor Inc.: Ralph Snodgrass or Douglass Given, (650) 617-0880.

Ohio University

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