• D A Roth, N E Tawa, J M O'Brien, D A Treco, R F Selden, and Factor VIII Transkaryotic Therapy Study Group.
• Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Mass 02115, USA. droth@caregroup.harvard.edu
• N. Engl. J. Med. 2001 Jun 7; 344 (23): 1735-42.

BackgroundWe tested the safety of a nonviral somatic-cell gene-therapy system in patients with severe hemophilia A.MethodsAn open-label, phase 1 trial was conducted in six patients with severe hemophilia A. Dermal fibroblasts obtained from each patient by skin biopsy were grown in culture and transfected with a plasmid containing sequences of the gene that encodes factor VIII. Cells that produced factor VIII were selected, cloned, and propagated in vitro. The cloned cells were then harvested and administered to the patients by laparoscopic injection into the omentum. The patients were followed for 12 months after the implantation of the genetically altered cells. An interim analysis was performed.ResultsThere were no serious adverse events related to the use of factor VIII-producing fibroblasts or the implantation procedure. No long-term complications developed, and no inhibitors of factor VIII were detected. In four of the six patients, plasma levels of factor VIII activity rose above the levels observed before the procedure. The increase in factor VIII activity coincided with a decrease in bleeding, a reduction in the use of exogenous factor VIII, or both. In the patient with the highest level of factor VIII activity, the clinical changes lasted approximately 10 months.ConclusionsImplantation of genetically altered fibroblasts that produce factor VIII is safe and well tolerated. This form of gene therapy is feasible in patients with severe hemophilia A.

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