Gene-based therapeutic strategies for Human Lipoprotein Lipase (LPL) deficiency: Rationale and prospects for alteration of atherogenic risk

Abstract

Lipoprotein lipase (LPL) plays a critical role in the regulation of total body lipoprotein and energy metabolism. This is evident in patients presenting with significant morbidity from profound hypertiglyceridemia due to complete LPL deficiency, such as infantile onset failure to thrive, hepatosplenomegaly, eruptive xanthomata, lipemia retinalis and chronic progressive pancreatitis. In addition, gene mutations leading to partial LPL deficiency may be common in the population and carriers often present with combined hyperlipidemia and hypercholesterolemia, which would be predicted to increase atherogenic risk. Conventional therapy by diet or lipid-lowering agents is often ineffective. The development of an alternative gene transfer-based therapy to potentiate LPL activity in patients with either complete or partial LPL deficiency would represent a major advance for persons suffering from this disorder. We report the current status of our efforts to develop and test a comprehensive series of vectors and delivery systems for LPL gene transfer and expression in somatic cells in vitro, and ultimately in vivo, in a well-characterized naturally occurring feline model with LPL deficiency.