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08-11-2010 | Cardiometabolic | Article

Gene therapy leads to marked regression of atherosclerosis


Free abstract

MedWire News: Using an adeno-associated virus 8 (AAV8) vector to restore expression of the low-density lipoprotein receptor (LDLR) gene could offer an approach to treating familial hypercholesterolemia (FH), an animal study suggests.

Intravenous injection of AAV8, incorporating mouse low-density lipoprotein receptor (mLDLR), causes sustained expression of the Ldlr protein, regression of atherosclerotic lesions, and significantly reduces plasma cholesterol levels in "humanized" mice, researchers report in the journal PLoS One.

Previous studies have shown that mice deficient in Ldlr and apolipoprotein B messenger RNA editing catalytic polypeptide-1 (Apobec1) (Ldlr-/-Apobec1-/-) simulate the metabolic and clinical aspects of homozygous FH (hoFH) in humans.

To investigate the efficacy of AAV8, Sadik Kassim (University of Pennsylvania, Philadelphia, USA) and colleagues delivered the mLDLR gene to the livers of Ldlr-/-Apobec1-/- mice at different doses (ranging from 1x1012 to 3x108 genome copies [GC]/mouse), and then measured for changes in their lipoprotein profiles.

A single intravenous injection of AAV8.mLDLR significantly reduced total cholesterol and non-high-density lipoprotein (non-HDL) cholesterol levels within 7 days. This was most pronounced at the highest treatment doses.

Even treatment with doses as low as 3x109 GC/mouse caused a decrease in total and non-HDL cholesterol levels, reducing them by 35% and 45%, respectively.

Kassim's team says that such a dose would translate to 3x1012 GC for a 20-kg adolescent person and 1x109 GC for a 70-kg adult, which is well within the reach of current manufacturing protocols.

An evaluation of the toxicologic effects of over-expressing mLDLR revealed no accumulation of hepatic cholesterol or hepatic triglycerides at any of the doses examined.

To investigate the efficacy of the vector further, the team tested for progression or regression of atherosclerotic lesions in Ldlr-/-Apobec1-/- mice. They quantified the total lesion area along the length of the aorta, and the percent aortic plaque compared with total aortic area, following AAV8.mLDLR injection.

Mice were fed a high-fat diet for 2 months, and then separated into three groups: injected with the AAV8.mLDLR vector; injected with a control vector; and no gene therapy. Mice given either vector were fed the high-fat diet for a further 2 months before measurement of atherosclerosis, while those given no gene therapy were measured directly (baseline mice).

The high-fat diet resulted in a 65% progression of atherosclerosis in mice injected with the control AAV8.null vector, compared with baseline mice.

In contrast, mice treated with AAV8.Mldlr had a 65% regression in atherosclerotic lesions. The researchers say: "This result represents the fastest and most substantial regression of atherosclerosis seen in a murine model after reduction in plasma cholesterol.

"Expression of LDLR via injection of AAV8.mLDLR induced marked reduction in cholesterol and substantial regression of atherosclerosis over 2 months."

The team suggests that AAV8-based in vivo gene therapy may be feasible for treatment of hoFH, and say they will support further development of this approach.

MedWire ( is an independent clinical news service provided by Current Medicine Group, a trading division of Springer Healthcare Limited. © Springer Healthcare Ltd; 2010

By Nikki Withers