Photo of grant trobridgeIn gene therapy, normal human genetic material stands a better chance of curing a disease if it gets a proper introduction into the patient’s chromosomes.

Dr. Grant Trobridge, assistant professor in the College of Pharmacy, has focused several years of research on perfecting that introduction. Use the wrong transfer agent – known as a vector – and it could make matters worse and even turn a normal target cell into a cancerous cell. The vector needs to be efficient, too. For some diseases a small percentage of corrected cells can provide a cure, but for others the therapeutic genes might need to hit as many as 3 out of 10 targets.

In gene therapy, normal DNA is introduced to replace, alter or supplement a defective gene responsible for causing a disease, with the expectation the new DNA will begin producing whatever has been missing or is defective and cure the disease.
After looking initially at a few different viruses used to introduce corrected DNA, Trobridge settled on working with the “foamy virus,” which is related to the more well-known human immunodeficiency virus (HIV). He has experimented with HIV some, but he prefers the foamy virus in part because it does not cause a disease.

“Some people might wonder why anyone would want to use vectors developed from viruses like HIV,” Trobridge said. “They work. You can alter them and cut out the disease-causing genes.” Key to the success of viral vectors is their ability to efficiently deliver genetic material to target cells, something foamy viruses have perfected over the last 30 million years. Trobridge and his colleagues spent the early years of this research engineering foamy vectors to efficiently deliver genes to blood cells, and once they were satisfied they had a vector that performed well, they began more recently to look at using it against specific diseases – all diseases of the blood system.

They also have had some success using bioinformatics – lots of human gene data accessible via computer – to identify the potential for an unwanted severe side effect of using viral vectors, which is that in some settings they can trigger a nearby normal gene to transform into a cancer gene. In these studies, they also compare different viral vectors for their relative toxicity to genes, which has led to a new area of research. “We are also now interested in using vectors to identify novel genes that are involved in hematopoiesis (blood cell production) and cancer,” Trobridge said. This new cancer research project is supported by a seed grant from the Donald J. and Margaret N. McLeod Endowment.

Trobridge is also funded by the National Institutes of Health to study the use of foamy vectors for gene therapy for Pyruvate Kinase Deficiency, an inherited and relatively rare disease of the red blood cells caused by a deficiency of the enzyme pyruvate kinase.  Success there could prove useful for more prevalent red blood cell diseases, he said. Trobridge also is studying the foamy vector’s use against other blood diseases like AIDS and SCID-X1, a rare immune system disorder known as the “bubble boy syndrome” because its victims need complete protection from germs.

Clinical trials of gene therapy for AIDS have revealed that a significant roadblock is inefficient delivery of the therapeutic DNA, Trobridge said. His team has had some success in AIDS research with a foamy vector, resulting in a more than 10,000-fold decrease in HIV replication in gene-modified cells. In this study the foamy vector allowed for efficient delivery to human blood cells in a mouse model.

Trobridge joined the College of Pharmacy faculty in May 2010 and received a WSU New Faculty Seed Grant for his research. He was a staff scientist at the Fred Hutchinson Cancer Research Center in Seattle and a research assistant professor in the Department of Medicine at the University of Washington. He has a Ph.D. in microbiology from Oregon State University.
(January 2011)