Adeno-associated virus LPL(S447X) 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) 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.
Rip
Jaap
J
Department of Vascular Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
Sierts
Jeroen A
JA
Vaessen
Stefan F C
SF
Kastelein
John J P
JJ
Twisk
Jaap
J
Kuivenhoven
Jan Albert
JA
D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000628:therapy*; D002784:Cholesterol / Q000097:blood; D000229:Dependovirus / Q000235:genetics*; D004041:Dietary Fats / Q000494:pharmacology; D005217:Fat Emulsions, Intravenous / Q000494:pharmacology; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007273:Injections, Intramuscular; D008071:Lipoprotein Lipase / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000502:physiology; D011973:Receptors, LDL / Q000235:genetics*; D014280:Triglycerides / Q000097:blood
D004041:Dietary Fats; D005217:Fat Emulsions, Intravenous; D011973:Receptors, LDL; D014280:Triglycerides; D002784:Cholesterol; D008071:Lipoprotein Lipase