Recapitulating the phenotype is the underlying basis for animal models of various disease states. Typically, this involves models created in the lab that closely resemble the cellular mechanisms of the human body.
Now, researchers at Baylor College of Medicine say they have generated a new disease model that more than just resembles the human mechanisms—it acts as a fully functional human lipid system within a mouse specifically to study hypercholesterolemia, a genetic disorder characterized by extremely high cholesterol levels.
“Diseases of lipid metabolism, such as hypercholesterolemia, can be deadly if not managed or treated, but there are no animal models that can closely recapitulate this type of human disease,” explained Karl-Dimiter Bissig, M.D., Ph.D., assistant professor in the Stem Cells and Regenerative Medicine Center at Baylor and senior author on the current study. “Within the model we created we were able to show the presence of certain proteins that are only found in humans, meaning the whole lipid machinery is present and can be used to study the disease within the model rather than just a cell structure created to resemble the machinery.”
The findings from this study were published today in Nature Communications through an article entitled “Development and rescue of human familial hypercholesterolaemia in a xenograft mouse model.”
Dr. Bissig and his colleagues utilized diseased human liver cells removed during surgical transplant and isolated the particular cells most affected by the genetic disorder. The researchers were then able to graft the isolated cells onto a mouse liver, resulting in a chimeric liver that can reach up to 95% humanization.
“By doing this we are now able to test a number of treatments and have a more accurate result of how certain treatments might actually affect human cells,” said Dr. Bissig.
The investigators explained that the hepatocytes that were xenograft onto the mouse came from a patient with familial hypercholesterolemia caused by loss-of-function mutations in the low-density lipoprotein receptor (LDLR). Moreover, much like human patients suffering from familial hypercholesterolemia, the chimeric mice developed hypercholesterolemia and a humanized serum profile.
“A lot of studies take place in mice models because there are a lot of similarities in the makeup of these two organisms, but there are obviously quite a few differences,” stated Dr. Bissig. “While this model does not mimic everything within the human lipid system, it is more similar than other models, which may speed up the process of bringing lab work to the bedside.”
Remarkably, the investigators replaced the missing LDLR in the chimeric mice using an adeno-associated virus 9-based gene therapy and were able to restore normal lipoprotein profiles after administration of just a single dose.
“Our study marks the first time a human metabolic disease is induced in an experimental animal model by human hepatocyte transplantation and treated by gene therapy,” the scientists conclude.