Blood Vessels in Tumors Targeted by Injectable Gene Therapy

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Researchers from Washington University School of Medicine in St. Louis, MO have recently developed an injectable viral vector that targets blood vessels of tumors, paving the way for new possibilities for gene therapy and its fight against cancer and other diseases that have abnormal blood vessels.

Such an accomplishment is a ground breaking result in the long search for a means of utilizing a deactivated virus to distribute disease-altering genes directly to target cells via injection into the bloodstream.

In a recent issue of the online open access journal PLoS ONE, the team reports how it used the method to target tumor blood vessels in mice without disturbing any surrounding healthy tissue.

Co-author and distinguished professor of radiation oncology, David T. Curiel, delineates the significance of such an achievement:

"Most current gene therapies in humans involve taking cells out of the body, modifying them and putting them back in. This limits gene therapy to conditions affecting tissues like the blood or bone marrow that can be removed, treated and returned to the patient. Today, even after 30 years of research, we can't inject a viral vector to deliver a gene and have it go to the right place," he said.

With this early "proof-of-concept" study, not only have Curieland his peers demonstrated the possibilities to use a deactivated virus to deliver those chosen genes directly to target cells in the lining of tumor blood vessels, but they have also managed to perform the task without the virus getting stuck in the liver, a difficutly that has long puzzled physicians.

During the course of the study, the team developed the viral vector to transport a gene load to target the abnormal blood vessels that feed and nurture tumor growth, but not to terminate them.

Instead, their goal was to demonstrate how it might be possible to utilize the tumor's own blood supply to fight the cancer.

"We don't want to kill tumor vessels. We want to hijack them and turn them into factories for producing molecules that alter the tumor microenvironment so that it no longer nurtures the tumor. Such a strategy could be used either to stop the tumor growth, or help chemotherapy and radiation to make them more effective. One advantage of this strategy is that it could be applied to nearly all of the most common cancers affecting patients," said professor of urologic surgery and of cell biology and physiology, and senior author of the study, Jeffrey M. Arbeit

According to Arbeit such a method may even be effective against other diseases, such as Alzheimer's, multiple sclerosis and heart failure that have abnormal blood vessels.

To show that they could get the vector to carry a gene that only reaches the target cells, the team had it carry a piece of the human roundabout4 (ROBO4) gene, which is known to be activated in the cells that line blood vessels in tumors.Gene therapy

They injected the viral vector and its load into the bloodstream of mice holding a variety of tumors and found it collected in tumor blood vessels, while largely avoiding healthy tissue.

Additionally, because the gene produces a protein in the target cells glow green, they could see that the vector reached only tumor vessels and avoided healthy tissue.

In their study, they explain a case where a kidney tumor spread to an ovary one of the mice. The team was able to show how the vessels feeding the secondary (metastatic) tumor glowed green, distinguishing it from the vessels in the healthy part of the ovary.

The researchers employed a combination of imaging techniques, such as "wide field low power, intermediate, and high power microscopic magnification bolstered by quantitative immunoblotting," to reveal that the viral vector specifically targeted the linings of blood vessels in both primary and metastatic cancers.

Moreover, the researchers discovered that by adding the anti-clotting agent warfarin, they could stop the viral vector colleting in the liver. The team says this worked because the warfarin halted the virus interacting with the mice's blood-clotting machinery.

However, the warfarin agent would not work in human patients due to the risk of bleeding, yet its value in the mouse study serves to show that it is possible to add something to the virus to stop it gathering in the liver. Prior studies suggest in human patients this could be achieved genetically.

"We combined a method we had developed to detarget the liver and a method to target the blood vessels. This combination allowed us to inject the vector into the bloodstream of the mouse, where it avoided the liver and found the proliferative vessels of interest to us," concluded Curiel.


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