ExeGen

® LDLR +/- MiniSwine

Heterozygous Genotype

This model features targeted disruption of the endogenous LDLR (low-density lipoprotein receptor) gene.

Background

In humans, loss-of-function mutations in LDLR lead to familial hypercholesterolemia, characterized by elevated plasma concentrations of cholesterol. Heterozygotes exhibit higher cholesterol levels and an increased risk for atherosclerosis.

Benefits of the Model:

  • Consistent, stable hypercholesterolemia that can be further modulated by diet

  • Predictable, progressive atherosclerosis that manifests on an accelerated timeline

  • Atherosclerotic lesion formation in the aorta and coronary arteries that model key pathophysiological aspects of human atherosclerosis

  • Defined Yucatan miniature swine genetics that offer greater consistency, smaller size, and lower cost to house and manage

Hypercholesterolemia
Characteristics:

ExeGen® heterozygote (LDLR+/-) MiniSwine are healthy at birth, with cholesterol levels similar to wild-type controls (LDLR+/+) when fed a normal diet (ND). However, when both groups are fed a Western-style diet (WD) for 25 weeks, the heterozygotes develop consistent, stable hypercholesterolemia, with significantly higher total cholesterol levels (>500 mg/dl) than in the control group. Like in humans, these levels are reduced when given a daily statin dose.

The Western-style diet was formulated to be more representative of human consumption containing natural sources of saturated fat and cholesterol.

Figure 1. Total Cholesterol Levels in LDLR+/- and LDLR+/+ MiniSwine on Normal and Western-Style Diets

Atherosclerosis Characteristics:

ExeGen® LDLR+/- MiniSwine fed a Western-style diet develop atherosclerotic lesions on an accelerated timeline.

Figure 2. Atherosclerotic lesions in the aorta of an 11 month old ExeGen® LDLR+/- MiniSwine fed a western-style diet for 6 months.

A. H&E staining of cross section; luminal side is at the top.

B. Magnification of insidicates area from A shows an plaque with possible proliferating smooth muscles cells.

Figure 3. Atherosclerotic lesions in the coronary arteries of an 11 month old ExeGen® LDLR+/- MiniSwine fed a western-style diet for 6 months.

A. H&E staining of the anterior descending artery shows an early plaque

B. Magnification of indicated region in A shows possible calcification.