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Nonviral Gene Therapy Method Seems Safe

Kate Traynor

A gene therapy technique that avoids the use of viral vectors seems safe in the treatment of patients with severe hemophilia A.

The experimental therapy involved the insertion of plasmid DNA encoding coagulation factor VIII into fibroblasts obtained from six men who lacked this sex-linked gene. The altered fibroblasts were grown in culture and laparoscopically transferred into each patient’s abdomen where, it was hoped, the cells would begin producing factor VIII.

None of the patients who participated in this Phase I study had a serious adverse reaction to the cell implantation procedure or the presence of the altered fibroblasts. Although the study was designed to test the safety of this gene therapy technique, the procedure seemed to show a clinical benefit. Factor VIII activity in four of the six patients increased temporarily after the cell-transfer procedure, and one patient’s bleeding tendency decreased for about 10 months.

The results of the study appeared in the June 7 New England Journal of Medicine.

The study participants, who were 20 to 72 years old, had less than 2.0 percent of the normal level of factor VIII activity when they entered the study. These men were considered to have severe hemophilia A. Each had had at least six bleeding episodes per year.

Three of the patients received implants totaling 100 million cells, and the other three were given 400 million cells apiece The three men who received the greater load of fibroblasts showed an increase in factor VIII activity after the cell transfer, as did one man in the 100-million-cell group. The best clinical response occurred in the man whose genetically altered cells were found before the transfer to produce the highest levels of factor VIII.

The increased factor VIII activity observed in the patients who responded to gene therapy was small. But the researchers noted that an increase in activity to levels as low as 1–2 percent of normal can reduce the number of spontaneous bleeding episodes in patients with hemophilia A.

None of the patients seemed to mount an immune response to the altered fibroblasts. The researchers attributed the lack of immunogenicity, in part, to the fact that the gene transfer was accomplished without using a viral vector. Instead, plasmid DNA containing the factor VIII gene was introduced into the patients' fibroblasts, which had been made porous by applying an electrical current to the cells. Fibroblasts containing the factor VIII gene were isolated and expanded in culture, then transferred back to the patients.

Funding for the study was provided by Transkaryotic Therapies Inc., which designed the plasmid-based gene-delivery system used in the study. Fifteen of the report’s 20 authors were employed by or had a financial interest in Transkaryotic Therapies.