Effect of alipogene tiparvovec (AAV1-LPL(S447X)) on postprandial chylomicron metabolism in lipoprotein lipase-deficient patients

Abstract

Background: Lipoprotein lipase-deficient (LPLD) individuals display marked chylomicronemia and hypertriglyceridemia associated with increased pancreatitis risk. The aim of this study was to determine the effect of i.m. administration of an adeno-associated viral vector (AAV1) for expression of LPL(S447X) in muscle (alipogene tiparvovec, AAV1-LPL(S447X)) on postprandial chylomicron metabolism and on nonesterified fatty acid (NEFA) and glycerol metabolism in LPLD individuals.

Methodology: In an open-label clinical trial (CT-AMT-011-02), LPLD subjects were administered alipogene tiparvovec at a dose of 1 × 10(12) genome copies per kilogram. Two weeks before and 14 wk after administration, chylomicron metabolism and plasma palmitate and glycerol appearance rates were determined after ingestion of a low-fat meal containing (3)H-palmitate, combined with (continuous) iv infusion of [U-(13)C]palmitate and [1,1,2,3,3-(2)H]glycerol.

Principal findings: After administration of alipogene tiparvovec, the triglyceride (TG) content of the chylomicron fraction and the chylomicron-TG/total plasma TG ratio were reduced throughout the postprandial period. The postprandial peak chylomicron (3)H level and chylomicron (3)H area under the curve were greatly reduced (by 79 and 93%, 6 and 24 h after the test meal, respectively). There were no significant changes in plasma NEFA and glycerol appearance rates. Plasma glucose, insulin, and C-peptide also did not change.

Conclusions/significance: Intramuscular administration of alipogene tiparvovec resulted in a significant improvement of postprandial chylomicron metabolism in LPLD patients, without inducing large postprandial NEFA spillover.

Trial registration: ClinicalTrials.gov NCT00891306.