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AAV1-LPL(S447X) gene therapy reduces hypertriglyceridemia in apoE2 knock in mice

, : AAV1-LPL(S447X) gene therapy reduces hypertriglyceridemia in apoE2 knock in mice. Biochimica et Biophysica Acta 1761(10): 1163-1168

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-LPLS447X 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-LPLS447X (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.


PMID: 16990047

DOI: 10.1016/j.bbalip.2006.08.008

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