CHAPEL HILL - Research on a rare inherited blood disorder known as Glanzmann's disease shows for the first time that it's possible to target specific types of cells during gene therapy and avoid the less effective -- and possibly more dangerous -- "shotgun" approach now used, according to a new University of North Carolina at Chapel Hill School of Medicine study.
With more work, the method could help treat a host of gene-related illnesses including various cancers, UNC-CH scientists say.
"Using techniques first developed by other investigators, we created a way of targeting the expression, or production, of genetic material in blood platelets without affecting red or white blood cells at the same time," said Dr. Gilbert C. White II, professor of medicine and director of UNC-CH's Center for Thrombosis and Hemostasis. "This offers great promise for improved treatment of inherited blood disorders such as hemophilia and conceptual support for using the approach for non-inherited illnesses such as cancer.
"For example, if you wanted to get poison genes into cancer cells but not into other healthy cells, one could attach the poison gene to specific promoters -- or pieces of DNA - that function only in cancer cells and not in others."
A report on the study appears in the Aug. 17 issue of the Proceedings of the National Academy of Sciences. Besides White, authors are Drs. David A. Wilcox, a former UNC-CH postdoctoral fellow now at the Medical College of Wisconsin; John C. Olsen, research assistant professor of medicine at UNC-CH; and Lori Ishizawa and Michael Griffith of Nexell Therapeutics Inc. of Irvine, Calif.
Wilcox said he and his colleagues concentrated on correcting primitive stem cells - sometimes considered "parent" cells -- capable of developing into more specialized large cells. Those younger monster cells, called megakaryocytes, form in bone marrow and eventually shatter into at least hundreds of particles that become blood platelets. The body uses platelets, which float around in the bloodstream, to plug wound sites to stop bleeding and heal cuts and other wounds.
The scientists focused on Glanzmann's disease - which, because of a missing protein, prevents platelets from functioning properly -- as a model system for their work. In the laboratory, they succeeded in correcting the protein defect in the parent cells by inserting healthy genes into DNA with the help of a harmless virus that penetrated the cell walls.
"This work is novel to gene therapy because the method successfully uses a promoter that targets a protein that was missing or defective in megakaryocytes and not in other cell types," Wilcox said. Conceivably, all sorts of healthy replacement genes or even drugs could be attached to identical or similar promoters and function as well as they did in platelets but without affecting unrelated cells and cell functions, he said. Extensive testing of "daughter" cells such as red cells and white cells confirmed the method worked only where it was supposed to. There was no potentially hazardous effect on other cells.
"We target the parent stem cells because we want the therapy to last for a long time in humans," Wilcox said. "That wouldn't be possible if we just targeted platelets since a platelet's life span in the bloodstream averages only 21 days."
Wilcox, who called the findings "exciting and potentially very important," said more advanced studies already are under way at UNC-CH. Mouse and human cell experiments, while still in preliminary stages, have progressed well so far, he said.
Journal
Proceedings of the National Academy of Sciences