GENE-BASED THERAPEUTIC STRATEGIES FOR HUMAN LIPOPROTEIN-LIPASE (LPL) DEFICIENCY - RATIONALE AND PROSPECTS FOR ALTERATION OF ATHEROGENIC RISK

Lipoprotein lipase (LPL) plays a critical role in the regulation of to tal body lipoprotein and energy metabolism. This is evident in patient s presenting with significant morbidity from profound hypertiglyceride mia due to complete LPL deficiency, such as infantile onset failure to thrive, hepatosplenomegaly, eruptive xanthomata, lipemia retinalis an d chronic progressive pancreatitis. In addition, gene mutations leadin g to partial LPL deficiency may be common in the population and carrie rs 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 dev elopment of an alternative gene transfer-based therapy to potentiate L PL activity in patients with either complete or partial LPL deficiency would represent a major advance for persons suffering from this disor der. We report the current status of our efforts to develop and test a comprehensive series of vectors and delivery systems for LPL gene tra nsfer and expression in somatic cells in vitro, and ultimately in vivo , in a well-characterized naturally occurring feline model with LPL de ficiency.