The HDL mimetic CER-001 remodels plasma lipoproteins and reduces kidney lipid deposits in inherited lecithin:cholesterol acyltransferase deficiency.

Chiara Pavanello,Giuliano Boscutti,Laura Calabresi,Giovanna De Maglio,Patrizia Tulissi,Arianna Strazzella,Marta Turri,Stefano Pizzolitto,Riccardo Nappi

doi:10.1111/joim.13404

Abstract

BackgroundKidney failure is the major cause of morbidity and mortality in familial lecithin:cholesterol acyltransferase deficiency (FLD), a rare inherited lipid disorder with no cure. Lipoprotein X (LpX), an abnormal lipoprotein, is primarily accountable for nephrotoxicity.MethodsCER‐001 was tested in an FLD patient with dramatic kidney disease for 12 weeks.ResultsInfusions of CER‐001 normalized the lipoprotein profile, with a disappearance of the abnormal LpX in favour of normal‐sized LDL. The worsening of kidney function was slowed by the treatment, and kidney biopsy showed a slight reduction of lipid deposits and a stabilization of the disease. In vitro experiments demonstrate that CER‐001 progressively reverts lipid accumulation in podocytes by a dual effect: remodelling plasma lipoproteins and removing LpX‐induced lipid deposit.ConclusionThis study demonstrates that CER‐001 may represent a therapeutic option in FLD patients. It also has the potential to be beneficial in other renal diseases characterized by kidney lipid deposits.

Highlights

Familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD, OMIM#245900) is a rare recessive disorder of HDL metabolism, due to loss-offunction mutations in the LCAT gene [1]
The worsening of kidney function was slowed by the treatment, and kidney biopsy showed a slight reduction of lipid deposits and a stabilization of the disease
In vitro experiments demonstrate that CER-001 progressively reverts lipid accumulation in podocytes by a dual effect: remodelling plasma lipoproteins and removing lipoprotein X (LpX)-induced lipid deposit

Summary

Introduction

Familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD, OMIM#245900) is a rare recessive disorder of HDL metabolism, due to loss-offunction mutations in the LCAT gene [1]. Glomerulosclerosis is the major cause of morbidity and mortality in FLD patients, and kidney failure occurs in the 4th–5th decade of life [2]. Excess of unesterified cholesterol cannot be sustained by plasma lipoproteins and forms an abnormal lipoprotein called lipoprotein X (LpX), which deposits in the glomerulus, inducing kidney damage [3]. Unesterified cholesterol is the only biochemical parameter so far able to identify patients with rapid deterioration of kidney function [2]. Kidney failure is the major cause of morbidity and mortality in familial lecithin:cholesterol acyltransferase deficiency (FLD), a rare inherited lipid disorder with no cure. Lipoprotein X (LpX), an abnormal lipoprotein, is primarily accountable for nephrotoxicity

Methods

Results

Conclusion