Cancer Treatment: a homing virus for targeted gene therapy
A viral vector selectively accumulating has been developed
in the blood vessels of cancerous tumors
NanoNewsNet based on materials from Washington University School of Medicine: Gene therapy method targets tumor blood vesselsScientists from the Washington University School of Medicine in St. Louis have developed a method of gene delivery that is extremely in demand in gene therapy.
They created a deactivated virus that, when injected into the blood, delivers one or another of the desired gene to the desired cells. In their preliminary experiments on mice, the researchers confirmed the fundamental possibility of targeting tumor blood vessels without negatively affecting healthy tissues.
"Most modern methods of gene therapy used to treat humans are associated with taking cells from the body, modifying them and returning them back to the patient's body," says David Curiel MD, Professor Emeritus of Radiation Oncology. "This limits the use of gene therapy to tissues that can be taken, processed and returned to the patient, in particular, blood and bone marrow. Today, after 30 years of research, we still cannot introduce a gene-carrying viral vector into the bloodstream and deliver the gene to the right place."
Professor Curiel and his colleagues from the Siteman Cancer Center at the University of Washington School of Medicine and Barnes-Jewish Hospital managed to develop a "self-guided injectable vector" – a deactivated virus, the target of which is the inner lining of the blood vessels of the tumor, not "stuck" in the liver – a problem that reduced the previous efforts of scientists have been nullified.
An article about the development was published in the free access journal PLOS ONE (Zhi Hong Lu et al., Transcriptional Targeting of Primary and Metastatic Tumor Neovasculature by an Adenoviral Type 5 Roundabout4 Vector in Mice).
Based on their previous work and the developments of other scientists, the researchers designed this viral vector in such a way that the genes they deliver are turned on only in abnormal blood vessels that provide the tumor with nutrition and energy. But unlike most treatments aimed at tumor vessels, scientists did not aim to deprive the tumor of blood supply.
"We don't want to destroy tumor vessels," says study leader Jeffrey Arbeit, MD, professor of urological surgery and cell biology and physiology. "We want to capture them and turn them into factories for the production of molecules that change the tumor microenvironment so that it no longer feeds the tumor. This can stop the growth of the tumor as such or increase the effectiveness of standard chemotherapy and radiation. One of the advantages of the new strategy is that it can be applied to almost all the most common cancers."
Theoretically, Professor Arbeit notes, this approach can be applied not only to cancer, but also to other diseases characterized by damage to blood vessels, including Alzheimer's disease, multiple sclerosis and heart failure.
The viral vector developed by American scientists contains a DNA fragment called Robo4, active in the cells lining the blood vessels of the tumor.
In experiments on mice, researchers have shown that when injected into the bloodstream, this viral vector accumulates to a much greater extent in the vascular network of the tumor than in the lungs, kidneys, heart and other healthy organs.
To make sure that viral vectors accumulate in tumors, avoiding healthy areas, the researchers used them to deliver a gene that simply made the cells lining the blood vessels glow green. The experiments were conducted on mice with tumors in the kidneys and kidney cancer cells in the skin. In this case, the primary kidney tumor has spread to the ovary. Viral vectors collected in the vessels of a metastatic tumor glow green. Red staining shows normal ovarian blood vessels (photo: JM Arbeit, DT Curiel).
In addition, the addition of the anticoagulant drug warfarin prevented the accumulation of vectors in the liver by blocking the interaction of viruses with components of the blood clotting system. Although the researchers emphasize that the treatment of cancer patients with warfarin is impossible due to the risk of bleeding, the previous work of their group showed the possibility of genetic manipulation of the viral vector to prevent its accumulation in the liver.
"We used a combination of targeting strategies," says Professor Curiel. "We have combined the method we developed for liver detargeting and the method that targets blood vessels. This combination allowed us to introduce the vector into the bloodstream of the mouse, and it bypassed the liver, finding the proliferating vessels of interest to us."
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