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Real Time MRI Advances for Gene Therapy

By Alexander Bernstein

For years, one of the greatest drawbacks to chemotherapy has been its potentially devastating side effects. Indeed, many individuals are unable to complete their treatment, or even be treated with a potentially more effective drug because of severe side effects that the body cannot bear.

Finally, a group of researchers at the University of California San Diego School of medicine may have a solution. Their break through idea? Real time MRI (magnetic resonance imaging) guided gene therapy. While chemotherapy typically affects and exposes nearly every human cell to potential side effects, Dr. Clark Chen, the vice chairman of neurosurgery at UC San Diego Health System, explains that with the help of the real time MRI, it is possible to “limit the presence of the active drug to just the brain tumor and nowhere else in the body.”

The structure of the enzyme yCD that Toca 511 secretes. It is the ability of this mutant enzyme to transform an anti-fungal drug into an anti-cancer drug in the brain that allows for specific cancer cell killing during gene therapy (via University of Washington).

Concentrating their efforts on the treatment of brain tumors, Dr. Chen and his team have pioneered the use of MRI navigational technology to directly inject novel gene therapy right into the actual tumors themselves. The premise behind the technique is that the MRI illuminates the tumors while leaving the rest of the brain untouched, allowing doctors to hone in specifically on the area of interest. The cancer cells are then further pegged down through injection of Toca 511, a bioengineered retrovirus with the capacity to infect solely cancer cells, thereby labeling them. The truly incredible thing about Toca 511, however, is that it has been modified in such a way as to secrete a triple mutant of an enzyme called ytidine deaminase (yCD), which then transforms the typically anti-fungal drug flucytosine (5-FC) into the cancer-killing drug 5-fluorouracil (5-FU). Thus, the drug introduction is very specific as cell killing can only occur where an introduced 5-FC drug comes in contact with the yCD enzyme. In other words, cell killing only occurs in the tumors themselves.

Brain tumors, especially glioblastomas, are some of the most deadly forms of cancer, with barely more than a third of all people diagnosed with a malignant tumor living over a year after diagnosis. Dr. Santosh Kesari, director of Neuro-oncology at the Moores Cancer Center, explains that the biggest problem with current treatments is likely that the drugs are unable to effectively enter the brain due to the blood-brain barrier and other natural protection mechanisms that actually work against the brain in this particular case. Dr. Kesari explains that the premise behind this technique is that “this MRI-guided approach will help us deliver this drug into the tumor directly to see if the drug is working.” Since 5-FC is able to travel past the brain blood barrier, and Toca 511 is injected directly into the tumors, this treatment should yield exciting information regarding the effectiveness of current drugs used for treatment and potentially improve treatment for various other cancers as well.

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