AAV1-LPL(S447X) gene therapy reduces hypertriglyceridemia in apoE2 knock in mice.
Intramuscular (IM) application of adeno-associated virus serotype 1 (AAV1) for the delivery of human lipoprotein lipase (hLPL) was previously shown efficacious in mice with chylomicronemia. The current study addresses whether AAV1-LPL(S447X) can reduce elevated triglyceride (TG) levels in mice with attenuated clearance of TG-rich remnant particles.


METHODS
Female mice, expressing human apoE2 but deficient for endogenous apoE (apoE2KI) received IM injections of AAV1-LPL(S447X) (n=6; 8 x 10(12) gc/kg; 4-sites) or PBS (n=5). Following lipid monitoring, the mice were challenged with intravenous Intralipid injections, and sacrificed 3 months after treatment.


RESULTS
In the mice that received LPL gene therapy, a marked increase of post-heparin hLPL protein levels (averaging 517+/-277 ng/mL vs. 4+/-3 ng/mL in apoE2KI-untreated) induced 20% reductions of fasting plasma TG levels (p<0.05). This was accompanied by two-fold increased TG clearance rates after Intralipid administration at 6 weeks after treatment (p<0.05). Post-mortem analyses revealed increased levels of TG (2-fold, p<0.005) and cholesterol (1.7-fold, p<0.001) in the treated muscles.


CONCLUSIONS
IM application of AAV1-LPL(S447X) is effective in reducing TG levels in a mouse model for type III dyslipidemia. Thus, hypertriglyceridemia caused by attenuated uptake of TG-rich lipoproteins can be alleviated by increasing lipolytic function of the skeletal muscle tissue.
Rip
Jaap
J
Academic Medical Center, Department of Vascular Medicine, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
van Dijk
Ko Willems
KW
Sierts
Jeroen A
JA
Kastelein
John J P
JJ
Twisk
Jaap
J
Kuivenhoven
Jan Albert
JA
D000818:Animals; D053329:Apolipoprotein E2 / Q000235:genetics*; D000229:Dependovirus / Q000235:genetics; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D015228:Hypertriglyceridemia / Q000628:therapy*; D007273:Injections, Intramuscular; D008055:Lipids / Q000097:blood; D008071:Lipoprotein Lipase / Q000097:blood / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009132:Muscles / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
D053329:Apolipoprotein E2; D008055:Lipids; D014280:Triglycerides; D008071:Lipoprotein Lipase