Abstract
Ex vivo gene therapy directed to the liver is being developed for the treatment of inherited metabolic diseases. Transplantation of hepatocytes that have been transduced with a low-density lipoprotein (LDL) receptor gene is a potential form of therapy for familial hypercholesterolemia (FH). We have demonstrated efficacy of ex vivo gene therapy for familial hypercholesterolemia in a rabbit animal model of this disease. In preparation for human trials, we describe in this report experiments in baboons for documentation of the feasibility and safety of autologous hepatocyte transplantation. Three baboons underwent a partial hepatectomy and their hepatocytes were isolated, cultured, and transduced with a retrovirus containing the human LDL receptor gene. The hepatocytes were harvested and infused into an indwelling catheter that had been placed into the inferior mesenteric vein at the time of liver resection. The baboons tolerated the procedures well and are being maintained and clinically evaluated for an indefinite time period. Follow-up evaluations have ranged from 3 to 8 months. Clinical evaluations have been unremarkable and blood chemistry and hematology determinations have stayed within normal limits.
Overview summary
An ex vivo gene therapy protocol for the treatment of familial hypercholesterolemia (FH), due to a deficiency of low-density lipoprotein (LDL) receptors, is underway at the University of Michigan by the authors. The protocol involves the removal of liver tissue, the growth of the autologous hepatocytes in culture, the insertion of the LDL receptor gene via retroviral-mediated gene transfer, and the infusion of the gene-corrected heptocytes into the portal circulation of the patient. The present paper reports a portion of the safety and feasibility data that were used by the regulatory committees to evaluate the FH gene therapy protocol.
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