Targeting gene therapy to specific cells

September 1997

Researchers at the University of Chicago Medical Center have developed the first practical method to restrict the activity of genes used for gene therapy to a specific cell type. This discovery, made in animals, neatly sidesteps one of the chief safety hurdles slowing the advance of gene therapy in humans.

By attaching a recently discovered "on-off" switch for gene expression, taken from a gene that is turned on only in smooth muscle cells--which play a crucial role in cardiovascular disease--the researchers were able to restrict the action of the inserted genes to that specific cell type.

The research, which used a specially prepared virus to insert the marker genes into animal models, is reported in the September 1, 1997 issue of the Journal of Clinical Investigation.

"The ability to direct a gene to a specific cell type and prevent expression in other cell types is a powerful new tool that allows us to bypass one of the most troubling safety concerns facing gene therapy," said Michael Parmacek, MD, assistant professor of medicine at the University of Chicago and director of the study. "For the first time, we can use a virus to insert a therapeutic gene into smooth muscle cells in the body without worrying about its potential effects on other tissues, such as the lungs or liver."

Most current gene therapy approaches rely on cold viruses, crippled so that they can't multiply within the body, to insert copies of potentially therapeutic genes into cells. While these viruses are extremely efficient, they infect many different cell types, making it difficult to direct new genes to only one.

But by placing the gene under the control of a "promoter"--an on-off switch for gene expression--from a gene (SM22a) that is expressed only in smooth muscle cells, Dr. Parmacek's team found that no matter which types of cells were infected, the gene was only "turned on" in smooth muscle cells.

Remarkably, no matter how the researchers injected the custom-made gene-delivery virus--whether into an artery, intravenously, or directly into muscle--gene expression was limited to the targeted cells.

The finding suggests that other promoters could restrict expression to other cell types.

"If we, as cardiologists, had to choose one cell type to start with, this would be our first choice," said Parmacek.

Smooth muscle cells surround blood vessels, regulating how they contract and expand. The proliferation of smooth muscle cells after a vessel injury is a major contributor to atherosclerosis and is the leading cause of re-blockage of arteries after angioplasty.

In 1995, University of Chicago researchers demonstrated that gene therapy, using a virus, could be used to combat restenosis following angioplasty in several animal models. (Published in Science, 27 January 1995)

"But until now, we hesitated to use these therapeutic viruses in humans due to our concern that they would indiscriminately infect all cells," said Dr. Parmacek. "The use of the SM22a promoter to target recombinant gene expression specifically to arterial smooth muscle cells alleviates many of our safety concerns and clears the path to human trials."

Smooth muscle cells also modulate airway resistance, a key factor in asthma, and gut motility, important in irritable bowel syndrome. Targeted gene therapy, which would affect smooth muscle cells but not skeletal muscle, holds promise for treatment of these and other disorders.

Other members of the research team included Steven Kim, Hua Lin, Eliav Barr, Lien Chu and Jeffrey Leiden of the departments of medicine and pathology at the University of Chicago. The research was supported by grants from the Public Health Service and the Falk Charitable Trust.

Summary:
University of Chicago researchers have developed the first practical method to limit activity of therapeutic genes to a specific cell type (smooth muscle cells), clearing a major safety hurdle facing gene therapy. These cells play a crucial role in cardiovascular disease, especially restenosis, asthma, irritable bowel syndrome and other disorders.

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