Why Some People Didn't Give Up on Gene Therapy

Gene therapy, a treatment for disease that involves the insertion of healthy or disease-fighting genes into a person's cells, has undergone something of a roller coaster ride of public approval. Although hotly contested from its inception due to suggested ethical and methodological flaws, its first use in 1990 on four-year old Ashanti DeSilva to alleviate the symptoms of a rare immune disorder seemed successful. The next decade, however, instead of being one of vindication for gene therapy advocates, was fraught with disappointment due both to technical problems with its application, and to grossly unethical handling of its use in people.

In 1999, Jesse Gelsinger, an eighteen-year old with a genetically inherited liver disease, died in a clinical trial for gene therapy. Subsequent investigations found that the researchers involved in the study acted unscrupulously in a number of ways, such as not reporting serious side effects experienced by other patients and not disclosing that monkeys had died after similar treatment in previous studies. This provided more ammunition for opponents of gene therapy. Then, in a clinical trial in the beginning of this decade two children developed leukemia-like symptoms, leading to a temporary ban on clinical trials for the method.

Clinical trials were resumed, but as you can see scientists studying gene therapy have had many obstacles to overcome in getting people to focus on the potential of the treatment, and the successes it has had. Thus, news coming from researchers at the Cedars-Sinai Medical Center will likely be reason for gene therapy proponents to celebrate.

The group recently completed a study using gene therapy in rats to attack glioblastoma (GBM), the most common type of brain cancer. GBM is especially lethal, with a prognosis of six to twelve months of life after diagnosis. It is also extremely hard to treat, as, by the time it is diagnosed it has usually spread to other brain areas, making it difficult to surgically remove a tumor without leaving cancer cells behind. The blood-brain barrier, a safety mechanism that prevents toxins in the blood from entering the brain, stops chemotherapeutic agents from getting to tumor cells in effective amounts. Dendritic cells, which are essential to the immune process as they present foreign antigens on their cell surface to stimulate the immune response, do not naturally occur in the brain. Thus, the tumor in GBM grows unchecked by the immune system. This growth also usually causes behavioral changes and cognitive deficits as the tumor affects other areas of the brain.

The scientists at Cedars-Sinai, using a viral vector (a virus used as a vehicle to carry genetic material), sent two proteins to the cancer cells in the rats’ brains. One of the proteins attracted dendritic cells to the brain, which resulted in an immune response that attacked the cancer cells. Another protein, when combined with an antiviral medication (ganciclovir), also killed tumor cells.

The study found this treatment increased survival to about 70%. In addition, any behavioral or cognitive deficits that were caused by the growing tumors disappeared after the tumor was destroyed. The ability to generate an immune response to the cancer cells was also retained by the rat's immune system. Thus, when cancer cells were re-introduced later on, the rat's immune system was able to kill them off on its own.

Obviously, the implications of having a successful treatment for this type of tumor are tremendous, not only for the management of brain cancer, but also for cancer research in general. Phase I clinical trials for the therapy have been scheduled to begin this year. Unfortunately, even if all goes well in clinical trials, this treatment is still years away from being utilized in practice due to the structure of FDA guidelines for drug development. It is, however, a new bright spot on the horizon for gene therapy. It should also be cause for excitement for everyone, gene therapy advocate or not, as it may represent a crucial step toward treating cancer, one disease that has often eluded even our best efforts to do so in the past.