Recent advances in hepatic gene transfer: more efficacy and less immunogenicity

Systemic enzyme deficiencies and lysosomal storage disorders are excellent targets for the treatment of genetic disease by in vivo gene transfer. To enable efficient delivery of therapeutic gene products into the systemic circulation, gene transfer to the liver has been extensively pursued. Hepatocytes are capable of overexpressing biologically active enzymes, such as coagulation factors (in the treatment of hemophilia) and lysosomal enzymes, and efficiently secrete these proteins into the blood stream. Sustained therapeutic expression and correction of rodent and canine animal models of human disease has been reported for a number of genetic disorders. This has been possible because of recent advances in vector development and optimization of their delivery. Viral vectors, in particular adeno-associated viral vectors and retroviral vectors, have yielded remarkable successes in the treatment of dogs with hemophilia or mucopolysaccharidosis. Such studies in large animals represent an important intermediate step toward clinical application, which has now been initiated in the case of hemophilia. Equally importantly, hepatic gene transfer has been demonstrated to induce immune tolerance to therapeutic transgene products.