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Radioactive Reporters Track Gene Therapy In Body

Scientists at UCLA's Jonsson Cancer Center have discovered a novel way to follow gene therapy through the body: A tracking system of "reporter" genes that can be attached to any gene therapy and used to monitor the therapy's behavior.

After the reporter genes and gene therapy are paired and infused into a patient, the patient receives an injection of a special radioactive molecule.

The reporter genes produce a protein that traps the radioactive molecules, and the radioactivity causes the regions of the body in which the reporter gene is present to glow "hot" during a positron emission tomography (PET) scan.

This allows physicians to locate the reporter genes paired with the gene therapy and establish a picture of the treatment at work.

"Basically, we've found a way to make the body transparent for gene therapy. No matter what gene therapy we give to a patient, we will be able to follow what it's doing and know if it's working safely and effectively," said Dr. Sanjiv Gambhir, a researcher at UCLA's Jonsson Cancer Center.

"Until now," he said, "there's been no reliable way to tell if, or how well, gene therapies are working once they've been administered to a patient. Are the therapies reaching intended sites in the body? How much remains there and for how long? Is the gene being turned on in unintended places? These are the critical questions that we're now poised to answer."

The technology is expected to help patients with cancer and other illnesses, such as cardiovascular disease, said Gambhir, who also is an associate professor at the UCLA School of Medicine's Crump Institute for Molecular Imaging and in the School's Department of Molecular & Medical Pharmacology.

The discovery is outlined in today's issue of the journal Nature Medicine. In the article, Gambhir and his colleagues describe the unique gene therapy tracking system they designed and tested in the laboratory.

UCLA researchers plan to test the tracking system in prostate cancer patients within a year, and are working with researchers at other institutions to help them evaluate other gene therapy studies for cancer patients.

"When the gene therapy is activated, so are the reporter genes. We can indirectly see what the gene therapy is doing because the reporter gene is mirroring the therapy's actions," Gambhir said.

Dr. R. Edward Coleman, a professor of radiology and director of nuclear medicine at Duke University Medical Center in Durham, N.C., described the tracking system as an "elegant technique to show us where genes administered for therapeutic purposes localize and how many of them accumulate in a given region in the body.

"This development has major implications for the use of gene therapy in patients," Coleman said.

Gambhir said that the critical step in creating an effective tracking system was designing reporter genes that could be linked with a variety of gene therapies.

"Previously, a researcher would have had to develop separate ways to track each gene," Gambhir said. "But with all-purpose reporter genes linked to a gene of interest, you don't have to develop a new system every time you want to study the behavior of a specific gene."

Gambhir said that the level of radiation in the molecules is comparable to that of an X-ray, and the radioactive molecules are eliminated within hours through urination.

The bladder is the only organ that cannot be studied using this technology because all of the radioactive molecules will eventually travel there, making it difficult to distinguish whether the radioactive molecules are targeting cancer cells or waiting to be eliminated.

The two kinds of reporter genes used in the tracking system were developed in the 1990s by the UCLA Gene Imaging Consortium at the Jonsson Cancer Center.

The early research by this group of scientists, which includes Gambhir and Drs. Jorge Barrio, Simon Cherry, Harvey Herschman, Michael Phelps and Nagichettiar Satyamurthy, established that these first-of-a-kind reporter genes can successfully be imaged by a PET camera.

Dr. Michael E. Phelps, UCLA's pharmacology chair, and his colleagues invented the PET scanner at UCLA in 1973. The medical imaging technology shows the body's organs functioning in real time, offering the gold standard for studying the brain, heart, various cancers and neurological disorders.

[Contact: Kambra McConnel, Kim Irwin ]






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