Adeno-associated virus LPLS447X gene therapy in LDL receptor knockout mice

Background Overexpression of lipoprotein lipase (LPL) protects against atherosclerosis in genetically engineered mice. We tested whether a gene therapy vector that delivers human (h) LPLS447X cDNA to skeletal muscle could induce similar effects. Methods LDL receptor knockout (LDLr−/−) mice were injected intramuscular (IM) with adeno-associated virus serotype 1 (AAV1) LPLS447X or PBS. Four weeks later they were started on an atherogenic diet for 12 weeks. After termination, atherosclerosis was assessed and homogenates of muscle and liver tissue were analyzed. Results AAV1-treated mice showed hLPL concentrations of 768 ± 293 ng/mL in post-heparin plasma associated with 48% reductions of fasting triglycerides (TG) levels (p < 0.0001). In the absence of an effect on total cholesterol (TC) levels, no effects on atherosclerosis were found. An increase in lipid content of injected muscles was accompanied by a significant decrease of TG (−20%, p < 0.0001) and free cholesterol (FC) content (−24%, p < 0.0001) in liver homogenates. Conclusions The data show that transgenic hLPLS447X on top of endogenous murine LPL reduces fasting TG levels in plasma but has no effect on atherosclerosis in LDLr−/− mice. While lipid accumulation in the injected muscle was anticipated, this coincided with an interesting decrease of both TG and FC in liver homogenates.