Research shows new potential for disabled retroviruses

Scientists have developed a new application for the use of retroviruses as a vector to transfer genetic information into cells. The findings give rise to a new set of applications for vectors and hold implications for improved cell therapies and treatments of other blood-based disorders.

From Cincinnati Children’s Hospital Medical Center:
Research shows new potential for disabled retroviruses

Scientists at Cincinnati Children’s Hospital Medical Center have developed a new application for the use of retroviruses as a vector to transfer genetic information into cells. The findings give rise to a new set of applications for vectors and hold implications for improved cell therapies and treatments of other blood-based disorders.

The study appears in the October 22 issue of the journal, Molecular Cell.

Retroviruses are a family of RNA-containing viruses (such as HIV) that have been used as a vector in medical science for years. Retroviruses usually infect cells by entering the cell and stably inserting their own genetic information in the genome of the cell, after having converted the RNA into DNA. Scientists have found that after deactivating the original trigger that causes disease, retroviruses can be used as an effective delivery mechanism to permanently introduce genetic information that can prevent or cure disease. Such safety-modified retroviruses are currently being tested in stem cell and gene therapy studies and trials.

In gene therapy, retroviruses are used to permanently introduce genetic information into cells. But laboratory tests and one clinical trial have shown that this kind of permanent manipulation can trigger an oncogene and the patient could develop cancer. A number of studies are underway to decrease or fully prevent this risk in future trials.

In the new Cincinnati Children’s study, scientists modified a mouse leukemia retrovirus to transfer messenger RNA. The mRNA modified cells that were transferred into protein by cells, but only temporarily, because the stable form of genetic information (DNA) is not formed.

This marks the first time that RNA information has been used as a delivery mechanism using retroviral vectors. By definition, the effects of mRNA are temporary instead of permanent. The application has also proven not to be toxic in that it can not trigger an oncogene.

“We introduced a transient form of genetic material that does not end up in the nucleus of the cell. In other words, we modified the biological properties of a cell without modifying the genome,” said Christopher Baum, MD, an adjunct associate professor of experimental hematology at Cincinnati Children’s and the study’s lead author.

In 2003, Dr. Baum established a research team in the Molecular and Gene Therapy Program at Cincinnati Children’s. of the Division of Experimental Hematology at Cincinnati Children’s under the direction of David Williams, MD. The team interacts closely with colleagues from the Laboratory for Experimental Cell Therapy, which Dr. Baum founded in 2001 at Hannover Medical School in Hannover, Germany, and still operates. His research is conducted in the laboratory of Christof von Kalle, MD, PhD, a physician/researcher at Cincinnati Children’s, noted for achievements in gene therapy research.

“It will be very interesting to see what level of expression and what duration of expression will be possible in different cell types. The success of using this application in stem cell research depends on how intense the expression is and how long it lasts,” von Kalle said. The Baum team continues to work on the study in an effort to determine useful applications for cell therapy.

The application, although it has not been tested in a clinical setting, holds promise in perfecting cell-based therapies. It could prove effective in altering the behavior of a cell in terms of what type of specialized cell it becomes.

Furthermore, the study shows that you can use the method to express an artificial protein that eliminates a designer gene from the cell or introduces a gene at a defined location in the genome. “These proteins act as scissors to open the chain of genetic information at a defined point or cut out a piece of the DNA.”

“The method can be used to remove a designer gene out of a cell. It may also be of interest to promote cells to produce daughter cells, to adopt novel functions (differentiation), or to guide their movement in the body,” Baum said.

Scientists continue to test the efficiency of this newly developed technology against disease models in a laboratory setting.

The study is funded with grants from the German Research Council and the Cincinnati Children’s Research Foundation.

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