By 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.
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.
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.
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.