Familial hypercholesterolemia (FH) is a condition characterised with elevated cholesterol and low density lipoprotein (LDL) in the blood causing an early onset of cardiovascular disease. There are several categories for FH but most commonly it is caused by a mutation in the LDL receptor (LDLR) gene, it is estimated that about 1 in 100-200 individuals have a mutation in LDLR.
The LDL receptor modulates the amount of LDL in the blood. A genetic mutation in LDLR would cause either reduced or no expression of the LDL receptor at all. Therefore, LDL would not be absorbed into the liver cells efficiently. This would result in high LDL levels in the blood which would cause further complications, as this can make individuals more prone to developing severe atherosclerosis and then coronary artery disease.
A mouse line was created which had a nonsense point mutation in the LDLR gene that mimicked an FH mutation (the mouse line was called LDLR E208X mutant mice). LDLR E208X mutant mice had no LDL receptor protein expression in the liver and subsequently went on to develop severe atherosclerosis after being fed a high-fat diet.
The mutant LDLR E208X mice that had been treated with CRISPR-Cas editing, had partial restoration in LDL receptor expression levels and had reduced cholesterol, LDL, and triglyceride blood levels. Interestingly, the mice also exhibited smaller plaque formation in the aorta compared to the control group. Therefore, the CRISPR-Cas editing had prevented the mice from developing severe atherosclerosis and the other complications of FH.
This therapy did partially restore function but it did not completely alleviate the disease phenotype. Thus this therapy needs more refinement if it is to be used by itself, or it could be used in conjunction with current FH treatments.