Normalization of Low-Density Lipoprotein Receptor Expression in Receptor Defective Homozygous Familial Hypercholesterolemia by Inhibition of PCSK9 With Alirocumab

Lambert G, Chatelais M, Petrides F et al.
J Am Coll Cardiol. 2014 Dec 2;64(21):2299-2300

In a research letter in J Am Coll Cardiol, French scientists have presented data in which they show that inhibition of PCSK9 with monoclonal antibodies can upregulate LDL-c-receptor (LDLR) expression  in most patients with homozygous familial hypercholesterolaemia (HoFH), who have at least one defective LDLR-allele.
Because PCSK9 is a circulating inhibitor of the LDLR, it is not expected to lower plasma LDL-c in HoFH patients who are receptor-negative. In receptor-defective individuals, who have reduced LDLR activity, however, significant LDL-c lowering is anticipated.

Human dermal fibroblasts were cultured in circumstances that maximally upregulate LDLR expression, and were then incubated with recombinant PCSK9, and treated or not with the PCSK9-antibody alirocumab.
PCSK9 lowered LDLR expression, which was restored by alirocumab in HeFH and non-FH control fibroblasts. In fibroblasts of receptor-negative HoFH patients on the other hand, LDLR expression was very low. PCSK9 did not affect LDLR expression, and neither did alirocumab.
In receptor-defective HoFH, PCSK9 did lower LDLR expression to the level seen in non-stimulated culture conditions, and alirocumab reversed LDLR to maximal expression levels.

These results are consistent with a pilot study with evolocumab, another antibody against PCSK9, which showed that LDL-c levels were reduced in 6 receptor-defective HoFH patients, but not in 2 receptor-negative HoFH.
These studies showed a large variability in response to treatment and maximal LDLR-expression, even among fibroblast cell lines harbouring the same genetic defect. This may explain why not all receptor-defective HoFH patients respond in the same way to treatment.

Find this article on Pubmed