New Gene Therapy Technique Results In Efficient Gene Delivery

June 09, 1998

BOSTON, Mass., June 5--Viruses are normally all together too good at entering our cells. But when scientists alter them to carry desirable genes for genetic therapy, they usually have difficulty getting into the cells where their cargo is needed. Harvard Medical School researchers seem to have overcome this obstacle by building these weighty, less pugnacious viruses a bridge.

The new technique links the virus and target cells by a bridge consisting of two proteins?the growth factor EGF and the receptor for a protein found on the avian leukosis virus (ALV). When applied to cultured cells, the protein bridge allowed the virus not only to bind but also enter the designated cell targets. The researchers report these findings in the June 9 Proceedings of the National Academy of Sciences.

"The novel thing here is that this delivery device works efficiently, which allows for the first time the possibility that we can use this approach to target any cell type we want," says John Young, associate professor of microbiology and molecular genetics. He developed the method in collaboration with graduate student Sophie Snitkovsky.

Most efforts to design in vivo gene delivery systems have focused on further modifying the virus, for example, by building into its envelope a structure that directs the virus to a specific cell type. But the tinkering appears to interfere with the ability of the virus to enter the cells.

"We wanted to find an approach where we could preserve as much as possible the normal virus envelope -cell receptor interaction," says Young. He and Snitkovsky created the EGF-ALV receptor protein bridge and applied it to a series of cell types, including one with the normal EGF receptor and one without. Only those cells with the EGF receptor bound the molecular bridge.

To see if the virus, once linked, could actually enter cells, the researchers introduced a gene conferring resistance to the antibiotic neomycin into the viruses. They added the gene-carrying viruses to the cells and then exposed the cells to neomycin. To their surprise, the researchers saw colonies--demonstrating cells had become resistant to neomycin and thus had been infected by the virus. In fact, a much higher percentage of the cells were infected than expected. "This is really quite remarkable. I think jumping up and down is the way you?d describe our reaction," says Young.

The success may be due in part to the simplicity of the ALV system. Unlike HIV, which uses multiple receptors, ALV seems to enter cells by a single receptor. While the ALV receptor thus appears to be uniquely suited to the protein bridge approach, EGF is only one of many possible protein partners. Young and Snitkovsky speculate the method could be used on a variety of cell surface markers, including those found on cancer cells. They are currently exploring other possibilities in conjunction with graduate student Adrienne Boerger and other colleagues at Harvard Medical School. They are also working on ways to deliver the protein bridge in vivo.

"The way I look upon this experiment is that it has opened the door to the possibility of targeting by this mechanism," says Young. "It solves that problem in tissue culture. Translating that to the in vivo situation is a major hurdle now."

Harvard Medical School

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