UNC study may improve gene therapy safety

February 23, 2004

CHAPEL HILL -- New research from the University of North Carolina at Chapel Hill may hold keys to improving the safety of human gene therapy.

The study showed that the messenger can be as important as the message: Viruses genetically engineered for use as delivery vehicles for transferring therapeutic genes into the body may alone influence gene expression, or which genes are turned on. Moreover, depending on the type of virus, they may do so in potentially harmful ways.

"This basically tells us that the messenger plays an important role in gene expression," said study co-author Dr. Richard J. Samulski, professor of pharmacology and director of UNC's Gene Therapy Center. "At the molecular level, a cascade of cell signaling events occurs irrespective of the therapeutic gene. This is something we didn't anticipate." The report will appear in the March issue of Molecular Therapy, the American Society of Gene Therapy's journal.

The study focused on two viruses: adenovirus and adeno-associated virus, or AAV. These viruses, when genetically engineered, have shown particular promise in laboratory studies as gene transfer vectors and have been used in more than 170 clinical trials.

Samulski and UNC co-author Dr. Jackie L. Stilwell, a postdoctoral researcher, reported there has been significant progress in understanding how viral gene therapy vectors behave in laboratory animals, in terms of acute toxicity effects.

However, they wrote, "systematic comparison of their effects upon cells at the molecular level has not been established." In that regard, the new research offers important new and potentially useful information for predicting the safety of gene delivery in people.

"The field has advanced so rapidly that we can now do toxicity profiles inside an individual cell," Samulski said. "And basically what we're doing here is asking what happens to the genome if a vector or virus comes into the cell."

In their experiments on cultured lung cells, Samulski and Stilwell used DNA microarray technology to examine gene expression. This technology can monitor the whole genome on a single silicon chip, giving researchers a better picture of the interactions among thousands of genes simultaneously by displaying patterns of gene expression.

Exposure to AAV either as an intact virus or as a recombinant vector shell affected gene expression minimally and in patterns not associated with potential harm to the host organism, the report said. In addition, exposure to the empty capsid of AAV - the protein coat of the virus devoid of DNA - also produced minimal response from the genes. For example, only 1.9 percent of genes showed changes in expression in cells infected by recombinant AAV.

In contrast, gene expression after exposure to intact adenovirus and recombinant adenovirus vector was much broader and included the activation of immune and stress response genes. Lung cells exposed to empty adenovirus capsid showed a decrease in changes in cellular gene expression, although some were related to stress response genes.

This study provides a systematic explanation for the relative safety profiles of two commonly used gene therapy vector classes, Samulski said.

"The take-home message here is we can now monitor the genes that get turned on when you put a vector on the cell," he said. "We can then make changes to the vectors and observe how their safety profiles improve prior to their use clinically."

"As we make architectural changes to the delivery system, we can see the cell's response to it," Stilwell added. "The study represents the start of a useful database of gene expression signatures for people involved in vector development."

The next step for the UNC researchers is to continue exploring the vector-associated gene expression signatures in other cell types and to extend the work to whole animals.

"I think everybody involved in designing vectors will continue to build on this database," Samulski said. "We're laying the foundation here for that to happen."

Samulski, a pioneer in AAV research, said the new study further confirms his choice to study and develop altered AAV for gene therapy. Along with its potential for fewer toxic effects than that of many other viruses studied for use in gene therapy, a gene delivered via AAV remains active in cells for months or even years, he added.

Last year, a form of gene therapy created and developed in Samulski's laboratory and based on AAV was approved by the U.S. Food and Drug Administration and given to children with Canavan disease, a rare, inherited neurological disorder. It marked the first FDA approval for clinical use of an AAV vector for gene therapy that was produced by a U.S. academic institution.
The new research was supported by grants from the National Institutes of Health and the Cystic Fibrosis Foundation.

UNC School of Medicine

Note: Contact Samulski at 919-962-3285 or rjs@med.unc.edu. Contact Stilwell at 919-966-0905 or stilwell@med.unc.edu. For a copy of the study, contact Les Lang (contact information below). School of Medicine contact: Les Lang, 919-843-9687 or llang@med.unc.edu

University of North Carolina Health Care

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