Therapeutic Levels Of Human Factor Research Articles

Section Review: Biologicals & Immunologicals: Gene therapy for haemophilia

Recently, there has been significant progress on the development of a gene therapy protocol for the treatment of haemophilia. Expression of physiologic levels of both human factors VIII and IX has been achieved in animal models, and correction of the disease phenotype has been demonstrated in haemophilia B dogs. Various durations of clotting factor expression in vivo have been observed. Adenoviral vector-mediated expression of therapeutic levels of human factor IX has been sustained for at least ten months in mice. Although research achievements have been substantial, several obstacles impede progress toward clinical trials. Improvements in gene transfer vehicles and delivery methods are needed to ensure safe and efficacious gene therapy. Specific issues currently under investigation include the persistence of clotting factor expression, procedures which allow re-administration of therapy, and host immune responses to treatment.

Gene therapy for hemophilia A: production of therapeutic levels of human factor VIII in vivo in mice.

Continuous delivery of factor VIII (FVIII) protein in hemophiliacs by gene therapy will represent a major clinical advance over the current practice of infrequent administration of purified FVIII. Conceptually, retroviral vectors that can permanently insert the FVIII gene into the DNA of the host cell appear the most suitable vehicles for this specific purpose. However, most retroviral vector systems have shown a poor performance in the production of FVIII from primary cells in vitro and in vivo. Here we report the retroviral-mediated gene delivery of a B-domain-deleted human FVIII by using the MFG vector system. This vector permitted efficient transduction of the majority of the primary cells in culture without the use of a selectable marker. High levels of FVIII were produced by various transduced primary cells in vitro. Upon transplantation of primary fibroblasts into mice, therapeutic levels of FVIII in the circulation were obtained for > 1 week. The capacity of primary cells to deliver the FVIII into the circulation was strongly dependent on the site of implantation. These results represent a major step forward in development of gene therapy for treating hemophilia A.