EFFECTIVE TREATMENT OF FAMILIAL HYPERCHOLESTEROLEMIA IN THE MOUSE MODEL USING ADENOVIRUS-MEDIATED TRANSFER OF THE VLDL RECEPTOR GENE

Liver directed gene transfer with adenoviral vectors is being consider ed for the treatment of several metabolic diseases, including familial hypercholesterolaemia (FH). Gene replacement therapy of human low den sity lipoprotein (LDL) receptor gene into the murine model of FH trans iently corrected the dyslipidaemia; however, humoral and cellular immu ne responses to LDL receptor developed - possibly contributing to the associated hepatitis and extinguishing of transgene expression. We eva luated an alternative strategy of ectopic expression in the liver of t he very low density lipoprotein (VLDL) receptor, which is homologous t o the LDL receptor but has a different pattern of expression. Infusion of recombinant adenoviruses containing the VLDL receptor gene correct ed the dyslipidaemia in the FH mouse and circumvented immune responses to the transgene leading to a more prolonged metabolic correction.