AAV gene therapy as a means to increase apolipoprotein (Apo) A-I and high-density lipoprotein-cholesterol levels: correction of murine ApoA-I deficiency

Background Inherited apolipoprotein (Apo) A‐I deficiency is an orphan disorder characterized by high‐density lipoprotein (HDL)‐cholesterol deficiency and premature atherosclerosis. Constitutive over‐expression of ApoA‐I might provide a means to treat this disease. The present study provides a comprehensive evaluation of adeno‐associated virus (AAV)‐mediated ApoA‐I gene delivery to express human (h)ApoA‐I and correct the low HDL‐cholesterol phenotype associated with ApoA‐I deficiency. Methods In an effort to maximize AAV‐mediated gene expression, we performed head‐to‐head comparisons of recombinant AAVs with pseudotype capsids 1, 2, 6 and 8 administered by different routes with the use of five different liver‐specific promoters in addition to cytomegalovirus as single‐stranded or as self‐complementary (sc) AAV vectors. Results Intravenous administration of 1 × 1013 gc/kg scAAV8, in combination with the liver‐specific promoter LP1, in female ApoA‐I−/− mice resulted in hApoA‐I expression levels of 634 ± 69 mg/l, which persisted for the duration of the study (15 weeks). This treatment resulted in full recovery of HDL‐cholesterol levels with correction of HDL particle size and apolipoprotein composition. In addition, we observed increased adrenal cholesterol content and a significant increase in bodyweight in treated mice. Conclusions The present study demonstrates that systemic delivery of a scAAV8 vector provides a means for efficient liver expression of hApoA‐I, thereby correcting the lipid abnormalities associated with murine ApoA‐I deficiency. Importantly, the study demonstrates that AAV‐based gene therapy can be used to express therapeutic proteins at a high level for a prolonged period of time and, as such, provides a basis for further development of this strategy to treat hApoA‐I deficiency. Copyright © 2009 John Wiley & Sons, Ltd.