Long-term correction of murine lipoprotein lipase deficiency with AAV1-mediated gene transfer of the naturally occurring LPL(S447X) beneficial mutation.
Human lipoprotein lipase (LPL) deficiency causes profound hypertriglyceridemia and life-threatening pancreatitis. We recently developed an adult murine model for LPL deficiency: LPL -/- mice display grossly elevated plasma triglyceride (TG) levels (>200-fold) and very low high-density lipoprotein cholesterol (HDL-C < 10% of normal). We used this animal model to test the efficacy of adeno-associated virus-mediated expression of hLPL(S447X) (AAV1-LPL(S447X)) in muscle for the treatment of LPL deficiency. Intramuscular administration of AAV1-LPL(S447X) resulted in dose-dependent expression of hLPL protein and LPL activity (up to 33% of normal murine levels) in postheparin plasma. Remarkably, visible hyperlipidemia was resolved within 1 week; plasma TG was reduced to near-normal levels (from 99.0 to 1.8 mmol/L), and plasma HDL-C was increased 6-fold (from 0.2 to 1.1 mmol/L). At 8 months after administration of AAV1-LPL(S447X), an intravenous lipid challenge showed efficient, near-normal clearance of plasma TG. Histologic analyses of injected muscle further indicated that abnormal muscle morphology observed in LPL -/- mice was reversed after treatment. Expression of therapeutic levels of LPL(S447X), and the subsequent beneficial effect on plasma lipid levels, has lasted for more than 1 year. We therefore conclude that AAV1-mediated transfer of LPL(S447X) into murine skeletal muscle results in long-term near-correction of dyslipidemia associated with LPL deficiency.
Ross
Colin J D
CJ
Department of Medical Genetics, University of British Columbia (UBC), Centre for Molecular Medicine and Therapeutics, Vancouver, B.C., Canada, V5Z-4H4.
Twisk
Jaap
J
Meulenberg
Janneke M
JM
Liu
Guoqing
G
van den Oever
Karin
K
Moraal
Ewoud
E
Hermens
Wim T
WT
Rip
Jaap
J
Kastelein
John J P
JJ
Kuivenhoven
Jan Albert
JA
Hayden
Michael R
MR
D000818:Animals; D000229:Dependovirus / Q000235:genetics* / Q000378:metabolism; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006949:Hyperlipidemias / Q000378:metabolism / Q000628:therapy; D008072:Hyperlipoproteinemia Type I / Q000378:metabolism / Q000628:therapy*; D007273:Injections, Intramuscular; D050356:Lipid Metabolism; D008055:Lipids / Q000097:blood; D008071:Lipoprotein Lipase / Q000235:genetics*; D008297:Male; D051379:Mice; D009132:Muscles / Q000166:cytology; D009154:Mutation
D008055:Lipids; D008071:Lipoprotein Lipase