UI researchers find way to possibly improve effectiveness of gene transfers

October 26, 1999

IOWA CITY, Iowa -- Gene transfer is a promising strategy that may eventually help to reverse or prevent many diseases, but in some cases there are glitches that must first be worked out.

A University of Iowa Health Care research team has found one possible way to eliminate a gene transfer hang-up related to cystic fibrosis. The researchers, led by Michael Welsh, M.D., UI professor of internal medicine, and physiology and biophysics, and a Howard Hughes Medical Institute investigator; David Wiemer, Ph.D., UI professor of chemistry; and John Lee, M.D., a UI otolaryngology resident, have found a way to make an essential binding process more effective.

Gene transfer involves using a vector, often a disabled cold virus, as a delivery vehicle to supply cells with healthy copies of flawed genes. For cystic fibrosis, this means delivering a normal copy of the cystic fibrosis gene to cells lining the bronchial airways. However, researchers have had difficulty getting the vectors to stick to the cells.

"The major problem is that the viruses we use to carry in a gene don't bind very well to the airway cells," Welsh said. "The first challenge is to improve binding."

There are two ways to solve the binding problem, Welsh explained. Researchers can either change the delivery vehicle (the vector) or change the recipient cell so viruses can bind to it.

"Most of the effort has been focused on the former, trying to modify the vector," Welsh said. "We decided to take a look at the latter, to modify the cell surface."

The researchers decided to alter the cell surface with a sugar because cells tolerate a wide variety of sugars and incorporate them into surface proteins. However, the researchers needed a novel sugar, one that would stand out as unique on the cell surface and which could serve as a molecular handle for attaching to the vector. This need led to collaboration with Wiemer in the UI Department of Chemistry. Wiemer's lab created a synthetic sugar that Lee tested on cells.

"We fed the cells the unique synthetic sugar," Lee said. "They took it up and displayed that new sugar on their surfaces."

The researchers then used the novel surface sugar as a platform on which to build a structure to bind the virus.

"The new molecule on the cell surface allowed us to build a receptor for the virus by using a series of molecular reactions," Lee explained. "The virus vector then used the new receptor to attach to the cell. We used adenovirus as a test system, but the approach could be used for other vectors."

The change in the cell-surface binding site made the gene transfer about 10 times more efficient, Welsh said. However, he noted that the system is not immediately applicable to humans. Some of the reagents that these researchers used would generate an immune response.

"We tested the idea to provide a proof of principle," Welsh said. "I would like to emphasize that this cannot be used in humans. However, by helping us to understand how the system works, and by providing us with new knowledge of how to circumvent existing barriers, this work will help us to design better methods for gene transfer."

Wiemer added, "The challenge now is to find other synthetic sugars that can be expressed more efficiently on the cell surface, minimize the possibility of an immune response and further improve gene transfer."

Although Welsh and his colleagues specifically focused on airway gene transfers, "this problem is not unique to the airways," Welsh said. "Many cells that one might wish to target lack specific receptors and the same strategy for improvement could be used for them."

The Welsh lab findings appeared in a past issue of the Journal of Biological Chemistry.

University of Iowa

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