Striated muscle gene therapy for the treatment of lipoprotein lipase deficiency
نویسندگان
چکیده
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.
منابع مشابه
Gene therapy for genetic lipoprotein lipase deficiency: from promise to practice.
Lipoprotein lipase (LPL) deficiency is a rare, hereditary disorder of lipoprotein metabolism characterised by severely increased triglyceride levels, and associated with an increased risk for pancreatitis. Since no adequate treatment modality is available for this disorder, we set out to develop an LPL gene therapy protocol. This paper focuses on the clinical presentation of LPL deficiency, sum...
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