Administration of the High-Density Lipoprotein Mimetic CER-001 for Inherited Lecithin–Cholesterol Acyltransferase Deficiency

Faguer, Stanislas; Colombat, Magali; Chauveau, Dominique; Bernadet-Monrozies, P.; Beq, Audrey; Delas, Audrey; Soler, V.; Labadens, Isabelle; Huart, Antoine; Benlian, Pascale; Schanstra, Joost P.

doi:10.7326/l20-1300

Cited by 14 publications

(16 citation statements)

References 4 publications

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“…Consistent with what was observed in the mouse model [9] and in a French FLD patient [14], CER-001 infusion reduced lipid deposits in the glomeruli in our patient. As expected, this effect was not elicited by changes in lipid levels, which remained largely stable, but rather by a normalization of the lipoprotein profile induced by CER-001.…”

Section: Discussionsupporting

confidence: 92%

“…The present report confirms the beneficial effects on the kidney of the HDL mimetic CER-001 previously observed in an experimental model [9] and in a single case of LCAT deficiency [14], and pro-vides novel insights into the mechanisms of kidney function stabilization exerted by the drug. Kidney disease is the primary cause of morbidity and mortality in FLD patients [1], and kidney transplantation is unavoidable in the majority of cases.…”

Section: Discussionsupporting

confidence: 88%

“…The present report confirms the beneficial effects on the kidney of the HDL mimetic CER‐001 previously observed in an experimental model [9] and in a single case of LCAT deficiency [14], and provides novel insights into the mechanisms of kidney function stabilization exerted by the drug.…”

Section: Discussionsupporting

confidence: 87%

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

et al. 2021

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Background.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. CER-001 was tested in an FLD patient with dramatic kidney disease for 12 weeks.Results. Infusions 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. Conclusion.This 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.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 88%

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

et al. 2021

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“…Small-molecule LCAT activators, eventually orally active, have been tested in vitro and proved to be able to activate not only wild-type but also some mutant LCAT [92,93], but their development is still in the preclinical phase. Finally, the HDL mimetic CER-001 recently proved to reduce albuminuria and increase podocyte functionality in a mouse model of FLD [94] and to stabilize renal function in an FLD patient [95].…”

Section: Ckd Progression In Lcat Deficiencymentioning

confidence: 99%

High-Density Lipoproteins and the Kidney

Strazzella

Ossoli

Calabresi

2021

Cells

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Dyslipidemia is a typical trait of patients with chronic kidney disease (CKD) and it is typically characterized by reduced high-density lipoprotein (HDL)-cholesterol(c) levels. The low HDL-c concentration is the only lipid alteration associated with the progression of renal disease in mild-to-moderate CKD patients. Plasma HDL levels are not only reduced but also characterized by alterations in composition and structure, which are responsible for the loss of atheroprotective functions, like the ability to promote cholesterol efflux from peripheral cells and antioxidant and anti-inflammatory proprieties. The interconnection between HDL and renal function is confirmed by the fact that genetic HDL defects can lead to kidney disease; in fact, mutations in apoA-I, apoE, apoL, and lecithin–cholesterol acyltransferase (LCAT) are associated with the development of renal damage. Genetic LCAT deficiency is the most emblematic case and represents a unique tool to evaluate the impact of alterations in the HDL system on the progression of renal disease. Lipid abnormalities detected in LCAT-deficient carriers mirror the ones observed in CKD patients, which indeed present an acquired LCAT deficiency. In this context, circulating LCAT levels predict CKD progression in individuals at early stages of renal dysfunction and in the general population. This review summarizes the main alterations of HDL in CKD, focusing on the latest update of acquired and genetic LCAT defects associated with the progression of renal disease.

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“…Interestingly, CER-001 appears to have a therapeutic target in inherited lecithin cholesterol acyltransferase (LCAT) deficiency as shown in an animal model [121] and in a series of patients [122], apparently by way of lipoprotein remodeling and particularly dramatic reduction of LpX. This beneficial effect occurs earlier than predictable and may offer a novel way of treatment for this serious condition [123].…”

Section: Direct Use Of Hdlmentioning

confidence: 99%

The Role of High-Density Lipoprotein Cholesterol in 2022

Sirtori

Corsini

Ruscica

2022

Curr Atheroscler Rep

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Purpose of the Review High-density lipoproteins (HDL) are responsible for the transport in plasma of a large fraction of circulating lipids, in part from tissue mobilization. The evaluation of HDL-associated cholesterol (HDL-C) has provided a standard method for assessing cardiovascular (CV) risk, as supported by many contributions on the mechanism of this arterial benefit. The present review article will attempt to investigate novel findings on the role and mechanism of HDL in CV risk determination. Recent Findings The most recent research has been aimed to the understanding of how a raised functional capacity of HDL, rather than elevated levels per se, may be responsible for the postulated CV protection. Markedly elevated HDL-C levels appear instead to be associated to a raised coronary risk, indicative of a U-shaped relationship. Summary While HDL-C reduction is definitely related to a raised CV risk, HDL-C elevations may be linked to non-vascular diseases, such as age-related macular disease. The description of anti-inflammatory, anti-oxidative and anti-infectious properties has indicated potential newer areas for diagnostic and therapeutic approaches. In the last two decades inconclusive data have arisen from clinical trials attempting to increase HDL-C pharmacologically or by way of recombinant protein infusions (most frequently with the mutant A-I Milano); prevention of stent occlusion or heart failure treatment have shown instead significant promise. Targeted clinical studies are still ongoing.

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Administration of the High-Density Lipoprotein Mimetic CER-001 for Inherited Lecithin–Cholesterol Acyltransferase Deficiency

Cited by 14 publications

References 4 publications

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

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

High-Density Lipoproteins and the Kidney

The Role of High-Density Lipoprotein Cholesterol in 2022

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