Abstract 16900: Gene Therapy With Alipogene Tiparvovec Results in Enhanced Post-Prandial Clearance of Low Density Chylomicrons in LPLD Patients
Introduction: Alipogene tiparvovec (Glybera®) is designed to express functionally active LPL in the muscle of lipoprotein lipase deficient (LPLD) patients. It consists of a DNA sequence coding for a naturally occurring LPL gene variant (LPLS447X) packaged in an adeno-associated vector serotype 1 (AAV1), administered by intramuscular injection. To establish a biomarker for long term efficacy of alipogene tiparvovec, LPLD patients enrolled in a clinical trial were subjected to an oral fat challenge to monitor their post-prandial response before and after therapy.
Methods: 5 LPLD patients were treated with a dose of 1x1012 genome copies (gc) per kg body weight, administered as a one-time series of intramuscular injections. At 2 weeks before and 14 weeks after administration, and following an overnight fast, patients were given a standard, low fat meal (13% fat, 65% carbohydrates, 22% protein) supplemented with a [3H]-palmitate tracer. At several time points over the subsequent 24-hour time frame, blood was drawn and a chylomicron (CM) enriched fraction was isolated by ultracentrifugation. The amount of tracer recovered in the total plasma as well as in the CM fraction was determined. Postprandial nonesterified fatty acid (NEFA) and glycerol appearance rates were determined using U-13C-palmitate and d5-glycerol tracers.
Results: Post-prandial clearance before therapy was confirmed to be inefficient with no or only a limited decline of the tracer in the CM fraction up to 24 hours. 14 weeks after alipogene tiparvovec, total plasma and chylomicron TG levels were reduced up to 10 fold with a strong and significant reduction of level of 3H in total plasma and a 91% reduction of 3H-chylomicron AUC over 24 hours (p = 0.03). 3H-chylomicron AUC after alipogene tiparvovec was of similar magnitude to that of 5 healthy subjects who ingested a high fat meal. No statistically significant change in NEFA and glycerol appearance rates was observed.
Conclusions: A one-time administration of alipogene tiparvovec results in normalized post-prandial clearance of CM 14 weeks after administration, without rebound increase in postprandial NEFA spillover. This effect is likely due to selective muscle LPL expression induced by intramuscular administration of alipogene tiparvovec.
- © 2010 by American Heart Association, Inc.