More than a decade ago, tiny biotechnology firm Genetic Therapy, Inc. (GTI), caught the attention of Swiss pharma giant, Sandoz AG. GTI cofounder, Dr. W. French Anderson, had claimed that injecting healthy genes into patients to replace damaged or defective ones could revolutionize the treatment of diseases like cystic fibrosis, hemophilia, and perhaps even cancer. Sandoz merged with Ciby-Geigy to create Novartis in 1996, and soon forged a partnership with GTI and later with SyStemix (Palo Alto, CA), which was pursuing a similar idea. Novartis eventually absorbed both partners in transactions valued at $834 million. But after several gene therapy projects failed in early stages, Novartis’ enthusiasm was tempered, and they reorganized the entire gene therapy unit in the late ‘90s. The company now focuses on oncolytic viruses to treat metastatic cancer. “If they are not leading the way, they are certainly close,” thinks Anderson, who now directs the Gene Therapy Laboratories at the University of Southern California School of Medicine and who consults for GTI. Back in 1990, Anderson conducted an early human gene transfer experiment, in an atmosphere of unbridled enthusiasm. The recipient, four-year-old Ashanti DaSilva, suffered from ADA deficiency. ADA patients are prone to infection, suffering from Severe Combined Immunodeficiency (SCID) or “bubble-boy” disease. Unfortunately, the investigators were unable to demonstrate convincing clinical benefit from the therapy. Indeed, many subsequent attempts at gene therapy failed. GTI's showcase gene therapy effort to treat glioblastoma, a deadly brain tumor, was no exception. GTI's strategy was simple. Mouse cells producing replication-deficient retrovirus carrying the thymidine kinase gene from Herpes Simplex Virus (HSV) were injected into the brain after the tumor mass had been surgically removed. The cells were expected to pump out virus that could infect any remaining cancer cells, rendering them sensitive to the antiviral drug ganciclovir—thereby killing them. Although the initial results were encouraging, when preliminary results of a large, international trial started to roll in, a different story emerged. The survival curves of patients who received the gene therapy were no different from the control group, and the project was cancelled. In a twist of fate, however, the name survived. “A suddenly very successful new leukemia drug needed a name quickly and company officials remembered “gleevec,” the name we had given the glioblastoma vector program,” recalls Anderson. Meanwhile, GTI's early-stage human tests of therapies for cystic fibrosis, breast cancer, and several rare genetic diseases were running into problems as well. One by one, these efforts were halted. The gene therapy program was scaled down, and operations of GTI and SyStemix were combined. “Novartis consolidated all gene therapy research at its facility in Gaithersburg, MD. Gene therapy research is now focused on the development of oncolytic adenoviruses for the treatment of metastatic cancer,” explains Sheldon Jones, vice president of communications at Novartis, and SyStemix works on stem cell technology. Despite the failures, Novartis remains committed to the field. The company just completed a $20 million (US) state-of-the-art facility in Gaithersburg—the Novartis Center of Excellence for gene therapy research. “The program is not as large as it was, but it is still a significant effort,” says Anderson. GTI seems bullish on the clinical potential of their oncolytic viruses. One GTI virus, OVA001, makes use of the E2F-1 promoter to drive the essential E1A gene, restricting viral replication to Rb-defective tumor cells—present in about 85 percent of tumors. Trying to push selectivity even further, GTI researchers have put E4 genes under the control of the human telomerase reverse transcriptase (hTERT) promoter—also reported to be selectively active in tumor cells— in combination with E2F-1 controlled E1A. A third vector uses E2F-1 to drive E1A, and incorporates the gene for macrophage colony-stimulating factor (GM-CSF) with the aim of inducing local inflammatory and systemic anti-tumor responses. The company claims that the vector demonstrates enhanced anti-tumor activity and a higher incidence of complete tumor regression compared to a vector that lacks the cytokine transgene when tested in a xenograft model, although none of these results have appeared in the peer-reviewed literature. Indeed, the company is tight-lipped when prodded for details about the clinical potential of its replication-selective oncolytic viruses. This is perhaps not surprising given the field's early reputation for overstating the technology's potential. “Currently, Genetic Therapy, Inc. does not have any active clinical trials using oncolytic adenoviruses. Several early developmental candidates have been identified, and they are in the preclinical testing phase. We anticipate initiation of a phase I clinical trial in 2004,” stated Jones. Stay tuned.
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Open Access
Jun 17, 2003
Sherwood Casjens 
