TY - JOUR
T1 - Adeno-associated virus LPL(S447X) gene therapy in LDL receptor knockout mice
AU - Rip, Jaap
AU - Sierts, Jeroen A.
AU - Vaessen, Stefan F. C.
AU - Kastelein, John J. P.
AU - Twisk, Jaap
AU - Kuivenhoven, Jan Albert
PY - 2007
Y1 - 2007
N2 - BACKGROUND: Overexpression of lipoprotein lipase (LPL) protects against atherosclerosis in genetically engineered mice. We tested whether a gene therapy vector that delivers human (h) LPL(S447X) cDNA to skeletal muscle could induce similar effects. METHODS: LDL receptor knockout (LDLr-/-) mice were injected intramuscular (i.m.) with adeno-associated virus serotype 1 (AAV1) LPL(S447X) 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 hLPL(S447X) 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
AB - BACKGROUND: Overexpression of lipoprotein lipase (LPL) protects against atherosclerosis in genetically engineered mice. We tested whether a gene therapy vector that delivers human (h) LPL(S447X) cDNA to skeletal muscle could induce similar effects. METHODS: LDL receptor knockout (LDLr-/-) mice were injected intramuscular (i.m.) with adeno-associated virus serotype 1 (AAV1) LPL(S447X) 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 hLPL(S447X) 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
U2 - https://doi.org/10.1016/j.atherosclerosis.2006.09.023
DO - https://doi.org/10.1016/j.atherosclerosis.2006.09.023
M3 - Article
C2 - 17087965
SN - 0021-9150
VL - 194
SP - 55
EP - 61
JO - Atherosclerosis
JF - Atherosclerosis
IS - 1
ER -