Proprotein Convertase Subtilisin Kexin Type 9 Inhibition for Autosomal Recessive Hypercholesterolemia—Brief Report

Abstract

Objective— Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors lower low-density lipoprotein (LDL) cholesterol in the vast majority of patients with autosomal dominant familial hypercholesterolemia. Will PCSK9 inhibition with monoclonal antibodies, in particular alirocumab, be of therapeutic value for patients with autosomal recessive hypercholesterolemia (ARH)? Approach and Results— Primary lymphocytes were obtained from 28 genetically characterized ARH patients and 11 controls. ARH lymphocytes treated with mevastatin were incubated with increasing doses of recombinant PCSK9 with or without saturating concentrations of alirocumab. Cell surface LDL receptor expression measured by flow cytometry and confocal microscopy was higher in ARH than in control lymphocytes. PCSK9 significantly reduced LDL receptor expression in ARH lymphocytes albeit to a lower extent than in control lymphocytes (25% versus 76%, respectively), an effect reversed by alirocumab. Fluorescent LDL cellular uptake, also measured by flow cytometry, was reduced in ARH lymphocytes compared with control lymphocytes. PCSK9 significantly lowered LDL cellular uptake in ARH lymphocytes, on average by 18%, compared with a 46% reduction observed in control lymphocytes, an effect also reversed by alirocumab. Overall, the effects of recombinant PCSK9, and hence of alirocumab, on LDL receptor expression and function were significantly less pronounced in ARH than in control cells. Conclusions— PCSK9 inhibition with alirocumab on top of statin treatment has the potential to lower LDL cholesterol in some autosomal recessive hypercholesterolemia patients.

Homozygous Familial Hypercholesterolemia Patients With Identical Mutations Variably Express the LDLR (Low-Density Lipoprotein Receptor)

“…Homozygous familial hypercholesterolemia (HoFH) is a severe inherited disorder of lipoprotein metabolism resulting mostly from the presence of mutations on both alleles of the LDL receptor ( LDLR ) or in rare instances biallelic mutations of apolipoprotein B ( APOB ), proprotein convertase subtilisin kexin type 9 ( PCSK9 ) or the LDLR adaptor protein ( LDLRAP1 ) 1–3 . These genetic defects sharply reduce the hepatic clearance of low-density lipoproteins (LDL).…”

The Proprotein Convertases in Hypercholesterolemia and Cardiovascular Diseases: Emphasis on Proprotein Convertase Subtilisin/Kexin 9

“…Similar results were also observed in ARH-negative lymphocytes (Fasano et al, 2009), revealing the presence of an ARH-independent pathway for PCSK9 activity on LDLR. The presumed relatively lower contribution of this pathway in human liver (Thedrez et al, 2016) is yet to be unambiguously validated.…”

“…Although it was reported that in mice the cytosolic adaptor protein ARH is essential for the ability of extracellular PCSK9 to enhance the degradation of the LDLR in liver hepatocytes , recent clinical trials using an inhibitory PCSK9 mAb Alirocumab revealed that absence of ARH in some autosomal recessive hypercholesterolemic patients, although reducing the activity of PCSK9, still left room for an ARH-independent pathway, at least as ascertained in lymphocytes (Thedrez et al, 2016). Similar results were also observed in ARH-negative lymphocytes (Fasano et al, 2009), revealing the presence of an ARH-independent pathway for PCSK9 activity on LDLR.…”

Expression of LDLRs (Low-Density Lipoprotein Receptors), Dyslipidemia Severity, and Response to PCSK9 (Proprotein Convertase Subtilisin Kexin Type 9) Inhibition in Homozygous Familial Hypercholesterolemia

“…The authors compared ex vivo LDLR expression on the cell surface of lymphocytes (an accepted surrogate of hepatocyte LDLR expression) 17 in 22 HoFH patients with 1 normolipidemic individual and 5 HeFH patients. Experiments followed a rigorous sequence previously used by the authors 18 that simulate lipid-lowering treatments usually prescribed to FH patients, including stimulation of LDLR expression by 3-hydroxy-3-methylglutaryl-coenzyme reductase inhibition with mevastatin, incubation with recombinant PCSK9 to facilitate LDLR degradation, and incubation with a PCSK9 neutralizing antibody. Ten patients were simple homozygotes for the same LDLR mutations, whereas 5 were identical compound heterozygotes and 1 was homozygous for a pathogenic APOB variant that reduced ligand affinity but did not affect receptor activity.…”