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Striated muscle gene therapy for the treatment of lipoprotein lipase deficiency.

Striated muscle gene therapy for the treatment of lipoprotein lipase deficiency.
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Gadek KE, Wang H, Hall MN, Sungello M, Libby A, MacLaskey D, Eckel RH, Olwin BB,


Gadek KE, Wang H, Hall MN, Sungello M, Libby A, MacLaskey D, Eckel RH, Olwin BB, (click to view)

Gadek KE, Wang H, Hall MN, Sungello M, Libby A, MacLaskey D, Eckel RH, Olwin BB,

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PloS one 2018 01 0513(1) e0190963 doi 10.1371/journal.pone.0190963
Abstract

Excessive circulating triglycerides due to reduction or loss of lipoprotein lipase activity contribute to hypertriglyceridemia and increased risk for pancreatitis. The only gene therapy treatment for lipoprotein lipase deficiency decreases pancreatitis but minimally reduces hypertriglyceridemia. Synthesized in multiple tissues including striated muscle and adipose tissue, lipoprotein lipase is trafficked to blood vessel endothelial cells where it is anchored at the plasma membrane and hydrolyzes triglycerides into free fatty acids. We conditionally knocked out lipoprotein lipase in differentiated striated muscle tissue lowering striated muscle lipoprotein lipase activity causing hypertriglyceridemia. We then crossed lipoprotein lipase striated muscle knockout mice with mice possessing a conditional avian retroviral receptor gene and injected mice with either a human lipoprotein lipase retrovirus or an mCherry control retrovirus. Post-heparin plasma lipoprotein lipase activity increased for three weeks following human lipoprotein lipase retroviral infection compared to mCherry infected mice. Human lipoprotein lipase infected mice had significantly lower blood triglycerides compared to mCherry controls and were comparable to wild-type blood triglyceride levels. Thus, targeted delivery of human lipoprotein lipase into striated muscle tissue identifies a potential therapeutic target for lipoprotein lipase deficiency.

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