Clinical protocol of human gene transfer for hemophilia B.

Abstract

Hemophilia B due to deficiency of the human factor IX is a fatal hereditary disease. The transfusion of blood or concentrated factor IX is the normal way of treatment, but this may engender greater risks of infection of HIV and hepatitis virus. Thus we propose to treat the disease by the injection of human factor IX gene-corrected autologous skin fibroblasts. The vectors are XL-IX and N2CMV-IX, in which the human factor IX cDNA is driven by the LTR (for XL-IX) or hCMV (for N2CMV-IX) while the neo gene is driven by the SV40 early gene promoter. The packaging line is PA317. The protocol is designed in two phases. In Phase I, autologous gene-corrected skin fibroblasts would be injected in low numbers in order to see whether any side effects appear. In Phase II, about one billion gene-corrected cells would be injected several times and the patient would be monitored in order to determine if significant clinical improvement has occurred. Hemophilia B (Christmas disease), of which the mechanism is the mutation or deletion of the factor IX gene, is an inherited X-chromosome linked bleeding disorder caused by the deficiency or inactivity of the clotting factor IX. The only treatment available is passive: the transfusion of human blood or concentrated factor IX, which may increase the risk of infection with HIV or hepatitis virus. Thus we propose to attempt to use gene therapy to avoid these kinds of risks. The procedure would be to derive skin fibroblasts from the patients, grow the cells in alpha-MEM, insert a normal human factor IX cDNA into them using a process called retroviral-mediated gene transfer, and then return the gene-corrected cells to the patient. The protocol is designed in two phases. In Phase I, autologous gene-corrected skin fibroblasts would be injected in low numbers in order to see whether any side effects appear. In Phase II, about one billion gene-corrected cells would be injected several times and the patient would be monitored in order to determine if significant clinical improvement has occurred.