Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Pavanello C

PROVIDER: S-EPMC9299003 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Pavanello Chiara C Turri Marta M Strazzella Arianna A Tulissi Patrizia P Pizzolitto Stefano S De Maglio Giovanna G Nappi Riccardo R Calabresi Laura L Boscutti Giuliano G

Journal of internal medicine 20211111 3

<h4>Background</h4>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.<h4>Methods</h4>CER-001 was tested in an FLD patient with dramatic kidney disease for 12 weeks.<h4>Results</h4>Infusions of CER-001 normalized the lipoprotein profile, with a disappearance of the abnormal LpX in favou ...[more]

PMID: 34761839

Similar Datasets

Project description:ObjectiveCER-001 is a novel engineered HDL-mimetic comprised of recombinant human apoA-I and charged phospholipids that was designed to mimic the beneficial properties of nascent pre-ß HDL. In this study, we have evaluated the dose-dependent regulation of ABCA1 expression in vitro and in vivo in the presence of CER-001 and native HDL (HDL3).Methods and resultsCER-001 induced cholesterol efflux from J774 macrophages in a dose-dependent manner similar to natural HDL. A strong down-regulation of the ATP-binding cassette A1 (ABCA1) transporter mRNA (- 50%) as well as the ABCA1 membrane protein expression (- 50%) was observed at higher doses of CER-001 and HDL3 compared to non-lipidated apoA-I. In vivo, in an apoE-/- mouse "flow cessation model," in which the left carotid artery was ligatured to induce local inflammation, the inhibition of atherosclerotic plaque burden progression in response to a dose-range of every-other-day CER-001 or HDL in the presence of a high-fat diet for two weeks was assessed. We observed a U-shaped dose-response curve: inhibition of the plaque total cholesterol content increased with increasing doses of CER-001 or HDL3 up to a maximum inhibition (- 51%) at 5 mg/kg; however, as the dose was increased above this threshold, a progressively less pronounced inhibition of progression was observed, reaching a complete absence of inhibition of progression at doses of 20 mg/kg and over. ABCA1 protein expression in the same atherosclerotic plaque was decreased by-45% and-68% at 50 mg/kg for CER-001 and HDL respectively. Conversely, a-12% and 0% decrease in ABCA1 protein expression was observed at the 5 mg/kg dose for CER-001 and HDL respectively.ConclusionsThese data demonstrate that high doses of HDL and CER-001 are less effective at slowing progression of atherosclerotic plaque in apoE-/- mice compared to lower doses, following a U-shaped dose-response curve. A potential mechanism for this phenomenon is supported by the observation that high doses of HDL and CER-001 induce a rapid and strong down-regulation of ABCA1 both in vitro and in vivo. In conclusion, maximally efficient HDL- or CER-001-mediated cholesterol removal from atherosclerotic plaque is achieved by maximizing macrophage-mediated efflux from the plaque while minimizing dose-dependent down-regulation of ABCA1 expression. These observations may help define the optimal dose of HDL mimetics for testing in clinical trials of atherosclerotic burden regression.

Project description:ImportanceCER-001 is a negatively charged, engineered pre-β high-density lipoprotein (HDL) mimetic containing apolipoprotein A-I and sphingomyelin. Preliminary studies demonstrated favorable effects of CER-001 on cholesterol efflux and vascular inflammation. A post hoc reanalysis of a previously completed study of intravenous infusion of CER-001, 3 mg/k, showed that the intravenous infusion in patients with a high coronary plaque burden promoted regression as assessed by intravascular ultrasonography.ObjectiveTo determine the effect of infusing CER-001 on coronary atherosclerosis progression in statin-treated patients.Design, setting, and participantsA double-blind, randomized, multicenter trial evaluating the effect of 10 weekly intravenous infusions of CER-001, 3 mg/kg, (n = 135) or placebo (n = 137) in patients with an acute coronary syndrome (ACS) and baseline percent atheroma volume (PAV) greater than 30% in the proximal segment of an epicardial artery by intravascular ultrasonography. The study included 34 academic and community hospitals in Australia, Hungary, the Netherlands, and the United States in patients with ACS presenting for coronary angiography. Patients were enrolled from August 15, 2015, to November 19, 2016.InterventionsParticipants were randomized to receive weekly CER-001, 3 mg/kg, or placebo for 10 weeks in addition to statins.Main outcomes and measuresThe primary efficacy measure was the nominal change in PAV from baseline to day 78 measured by serial intravascular ultrasonography imaging. The secondary efficacy measures were nominal change in normalized total atheroma volume and percentage of patients demonstrating plaque regression. Safety and tolerability were also evaluated.ResultsAmong 293 patients (mean [SD] age, 59.8 [9.4] years; 217 men [79.8%] and 261 white race/ethnicity [96.0%]), 86 (29%) had statin prior use prior to the index ACS and 272 (92.8%) had evaluable imaging at follow-up. The placebo and CER-001 groups had similar posttreatment median levels of low-density lipoprotein cholesterol (74 mg/dL vs 79 mg/dL; P = .15) and high-density lipoprotein cholesterol (43 mg/dL vs 44 mg/dL; P = .66). The primary efficacy measure, PAV, decreased 0.41% with placebo (P = .005 compared with baseline), but not with CER-001 (-0.09%; P = .67 compared with baseline; between group differences, 0.32%; P = .15). Similar percentages of patients in the placebo and CER-001 groups demonstrated regression of PAV (57.7% vs 53.3%; P = .49). Infusions were well tolerated, with no differences in clinical and laboratory adverse events observed between treatment groups.Conclusions and relevanceInfusion of CER-001 did not promote regression of coronary atherosclerosis in statin-treated patients with ACS and high plaque burden.Trial registrationClinicalTrials.gov Identifier: NCT2484378.

Project description:AimHigh-density lipoproteins (HDLs) have several potentially protective vascular effects. Most clinical studies of therapies targeting HDL have failed to show benefits vs. placebo.ObjectiveTo investigate the effects of an HDL-mimetic agent on atherosclerosis by intravascular ultrasonography (IVUS) and quantitative coronary angiography (QCA).Design and settingA prospective, double-blinded, randomized trial was conducted at 51 centres in the USA, the Netherlands, Canada, and France. Intravascular ultrasonography and QCA were performed to assess coronary atherosclerosis at baseline and 3 (2-5) weeks after the last study infusion.PatientsFive hundred and seven patients were randomized; 417 and 461 had paired IVUS and QCA measurements, respectively.InterventionPatients were randomized to receive 6 weekly infusions of placebo, 3 mg/kg, 6 mg/kg, or 12 mg/kg CER-001.Main outcome measuresThe primary efficacy parameter was the nominal change in the total atheroma volume. Nominal changes in per cent atheroma volume on IVUS and coronary scores on QCA were also pre-specified endpoints.ResultsThe nominal change in the total atheroma volume (adjusted means) was -2.71, -3.13, -1.50, and -3.05 mm(3) with placebo, CER-001 3 mg/kg, 6 mg/kg, and 12 mg/kg, respectively (primary analysis of 12 mg/kg vs. placebo: P = 0.81). There was also no difference among groups for the nominal change in per cent atheroma volume (0.02, -0.02, 0.01, and 0.19%; nominal P = 0.53 for 12 mg/kg vs. placebo). Change in the coronary artery score was -0.022, -0.036, -0.022, and -0.015 mm (nominal P = 0.25, 0.99, 0.55), and change in the cumulative coronary stenosis score was -0.51, 2.65, 0.71, and -0.77% (compared with placebo, nominal P = 0.85 for 12 mg/kg and nominal P = 0.01 for 3 mg/kg). The number of patients with major cardiovascular events was 10 (8.3%), 16 (13.3%), 17 (13.7%), and 12 (9.8%) in the four groups.ConclusionCER-001 infusions did not reduce coronary atherosclerosis on IVUS and QCA when compared with placebo. Whether CER-001 administered in other regimens or to other populations could favourably affect atherosclerosis must await further study. Name of the trial registry: Clinicaltrials.gov; Registry's URL: http://clinicaltrials.gov/ct2/show/NCT01201837?term=cer-001&rank=2;Trial registration numberNCT01201837.

Dataset Information

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

Background

Methods

Results

Conclusion

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets