ExeGen® LDLR miniswine offers improved translational value to human clinical trials
MPI Research and Exemplar Genetics today announced the first successful validation of a new genetically engineered miniature pig model, offering an attractive alternative to rodent models, of atherosclerosis. The ExeGen® LDLR miniswine is a pig model in which the LDL receptor (LDLR) gene is knocked out, resulting in a more accurate analogue to atherosclerosis in humans, providing increased value to human clinical trials.
“This is a remarkable milestone in the drug development industry,” said Dr. John Swart, President of Exemplar Genetics. “These new models allow researchers to obtain a better understanding of cardiovascular disease, and thus can accelerate the development of new therapies.”
Small animal models of atherosclerosis are frequently used in drug studies, but the results often fail to translate into the clinic. The ExeGen LDLR miniswine addresses the limitations of other animal models effectively and was successfully used in a study to evaluate the effects of a statin on the development and progression of atherosclerosis.
“Due to similarities of their cardiovascular systems and more human-like size, pigs have long been studied as models of human cardiovascular disease,” said Dr. Dale Mais, Director of Metabolic diseases and Endocrinology at MPI Research. “However, spontaneous atherosclerosis in conventional swine is rare. We collaborated with Exemplar Genetics on a study in which these genetically engineered miniature swine with targeted disruptions in one or both LDLR alleles proved to be useful translational models of hypercholesterolemia and atherosclerosis.”
Five groups of the pigs were fed either a normal diet or a high-fat diet for a six-month period. One of the high-fat groups additionally received a daily dose of a statin. Every two weeks during the study, a variety of clinical chemistry parameters were measured. At the end of the study, select arteries were collected, stained for lipid deposits, and quantitated. Sections of these arteries were also evaluated to detect morphological characteristics of the atherosclerotic plaques. At the completion of the study, ExeGen LDLR heterozygotes also had a higher percentage of Oil Red O positive fatty streaks on their aorta, femoral, and coronary arteries, an early indicator of atherosclerotic lesions, than wild type controls on the same high fat diet. A statin reduced these streaks.
“As expected, pigs fed a high-fat diet gained significantly more weight at six months,” said Dr. Mais. “The statin appeared to reduce this weight gain. There were significant increases in total cholesterol, HDL, and LDL in pigs fed the high-fat diet, and the group receiving the statin had reduced values of these parameters compared to controls, showing that a statin had a beneficial effect on lipid levels even in a high-fat diet scenario.”
The statin-induced improvement of hypercholesterolemia in the studied model emphasizes its translational value, and confirms it will be a significant tool in the future development of therapies for cardiovascular disease.