Cries of “reports of gene therapy’s death have been greatly exaggerated” tend to be in a never-ending cycle with “gene therapy is dead.” Judging by the recent Congress of the European Society for Gene and Cellular Therapy, it looks like the former is in the ascendant: there is no shortage of activity in both laboratory and clinic.
Many researchers continue down promising pathways or attempt to correct shortcomings of the past, while others explore previously un- and undercharted territories. From the types of genes being delivered and the vectors they arrive in, to where they are headed and what they are destined to accomplish, to the means of ensuring that they heed Hippocrates’ admonition to above all do no harm, gene-delivery research seems to be alive and well.
Much gene therapy uses viral vectors to deliver corrective genetic material, allowing the target to produce a protein that it normally should have made. Sometimes the virus will be engineered to encode a protein designed to directly kill a wayward cancer cell, or to make it recognizable by the immune system. And sometimes the viruses themselves do the killing.
Mutations that allow cells to become malignant—such as the loss of growth control or the loss of key components of the interferon pathways—often make them much more susceptible to viral infection.
Len Seymour, Ph.D.’s group at the University of Oxford takes advantage of that, using adenovirus as a cytotoxic agent against colorectal cancer. On a molar basis, adenovirus is about 109 more potent than chemotherapy agents, and about 105 more potent on the basis of weight, “because the agents can amplify themselves within the target cells, lyse the target cells, and then spread to adjacent cells. It’s a very powerful approach if you can use it properly.”
One problem is that wild-type adenovirus is toxic to the liver, where colorectal cancer tends to metastasize. Attempts to attenuate a wild-type virus so that it is not active in liver cells generally end up attenuating its potency in cancer cells as well, he explains. So why not make a virus that is inactivated by liver cells?
miR-122 is a hepatocyte-specific microRNA that recognizes and inactivates mRNAs with the appropriate binding site. Dr. Seymour’s lab engineered an adenovirus so it contains miR-122 binding sites in its genome and found that “the virus is completely neutralized when it gets into hepatocytes, but still retains the activity of the wild-type virus when it gets into tumor cells.”
Dr. Seymour has also been using forced evolution to develop adenoviruses specific for colorectal cancer through a spin-out company he founded, Hybrid Biosystems (now PsiOxus Therapeutics) in collaboration with Schering (now Bayer Schering Pharma). “It has lost the components it needs for normal cells, but in tumors the mutations tend to complement those deletions,” he explained.
The Class B adenovirus—for which humans do not have natural antibodies—is highly active in tumors, but “has no obvious activity in normal cells.” Clinical trials for hepatic metastatic colorectal cancer will begin later this year, with the virus being injected directly into the hepatic artery of patients.