Lifetime correction of genetic deficiency in mice with a single injection of helper-dependent adenoviral vector

Ideally, somatic gene therapy should result in lifetime reversal of genetic deficiencies. However, to date, phenotypic correction of monogenic hyperli pidemia in mouse models by in vivo gene therapy has been short-lived and as sociated with substantial toxicity. We have developed a helper-dependent ad enoviral vector (HD-Ad) containing the apolipoprotein (apo) E gene. A singl e Lv. injection of this vector completely and stably corrected the hypercho lesterolemia in apoE-deficient mice, an effect that lasted the natural life span of the mice. At 2.5 years, control aorta was covered 100% by atheroscl erotic lesion, whereas aorta of treated mice was essentially lesion-free. T here was negligible toxicity associated with the treatment. We also develop ed a method for repeated HID-Ad vector administration that could be applied to organisms, e.g., humans, with life spans longer than 2-3 years. These s tudies indicate that HID-Ad is a promising system for liver-directed gene t herapy of metabolic diseases.