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

BackgroundOverexpression 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.MethodsLDL 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.ResultsAAV1-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.ConclusionsThe 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.