Injectable gene therapy targets blood vessels in tumors

Date: Dec-27-2013By designing an injectable viral vector that targets blood vessels of tumors, researchers from

Washington University School of Medicine in St. Louis, MO, have opened new avenues for gene therapy

against cancer and other diseases that have abnormal blood vessels.

The achievement is a milestone in the long search for a way of using a deactivated virus to deliver disease-altering genes directly to target cells by injection into the bloodstream.

In a recent issue of the online open access journal PLoS ONE, the team reports how it used the approach to target tumor blood vessels in mice without harming healthy

tissue.

Co-author David T. Curiel, distinguished professor of radiation oncology, explains the importance of the

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."

With this early "proof-of-concept" study, not only have he and his colleagues shown it is possible - in mice

at least - to use a deactivated virus to carry chosen genes directly to target cells in the lining of tumor

blood vessels, but they also managed to do it without the virus getting stuck in the liver, something that has

eluded previous attempts.

Study aim was to show potential for other approaches

In their study, the team designed the viral vector to carry a gene payload to target the abnormal blood

vessels that drive and nurture tumor growth, but not to destroy them.

Instead, their goal was to show how it might be possible to use the tumor's own blood supply to fight the cancer, as senior author Jeffrey M.

Arbeit, professor of urologic surgery and of cell biology and physiology, explains:

"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," Prof. Arbeit adds.

In theory, he says, such an approach may even work against diseases other than cancer - such as Alzheimer's,

multiple sclerosis and heart failure - that feature abnormal blood vessels.

Targeted cells 'glowed green,' while healthy tissue did not

To show that they could get the vector to carry a gene that only reaches the target cells, the team got it

to carry a piece of the human roundabout4 (ROBO4) gene, which is known to be switched on in the cells

that line blood vessels in tumors.

They injected the viral vector and its payload into the bloodstream of mice bearing a range of tumors and

found it collected in tumor blood vessels, while largely avoiding healthy tissue.

Also, because the gene makes a protein in the target cells glow green, they could see that the

vector reached only tumor vessels and bypassed healthy tissue.

In their study, they describe a case where a kidney tumor spread to an ovary in the mouse. The team was able

to show how the vessels feeding the secondary (metastatic) tumor glowed green, distinct from the vessels in the

healthy part of the ovary.

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

Adding second factor to payload stops vector gathering in liver

In another part of their study, they found by adding the anti-clotting agent warfarin, they could stop the

viral vector gathering in the liver. The team says this worked because the warfarin stopped the virus

interacting with the mice's blood-clotting machinery.

However, the warfarin solution would not work in human patients because of the risk of bleeding, but 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. Previous studies suggest in human patients this could be done genetically.

Prof. Curiel sums up the achievement:

"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."

Funds from the National Institutes of Health (NIH) helped pay for the study.

In March 2011, another team of US researchers published a study where they described developing a nanodrug to fight breast cancer without harming

healthy tissue by targeting specific molecules that help tumors grow and spread.

Written by Catharine Paddock PhD

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