Randomized, Placebo-Controlled Phase 2b Study to Evaluate the Safety and Efficacy of Recombinant Human Lecithin Cholesterol Acyltransferase in Acute ST-Segment-Elevation Myocardial Infarction: Results of REAL-TIMI 63B.

BACKGROUND: High-density lipoprotein plays a key role in reverse cholesterol transport. In addition, high-density lipoprotein particles may be cardioprotective and reduce infarct size in the setting of myocardial injury. Lecithin-cholesterol acyltransferase is a rate-limiting enzyme in reverse cholesterol transport. MEDI6012 is a recombinant human lecithin-cholesterol acyltransferase that increases high-density lipoprotein cholesterol. Administration of lecithin-cholesterol acyltransferase has the potential to reduce infarct size and regress coronary plaque in acute ST-segment-elevation myocardial infarction. METHODS: REAL-TIMI 63B (A Randomized, Placebo­controlled Phase 2b Study to Evaluate the Safety and Efficacy of MEDI6012 in Acute ST Elevation Myocardial Infarction) was a phase 2B multinational, placebo-controlled, randomized trial. Patients with ST-segment-elevation myocardial infarction within 6 hours of symptom onset and planned for percutaneous intervention were randomly assigned 2:1 to MEDI6012 (2- or 6-dose regimen) or placebo and followed for 12 weeks. The primary outcome was infarct size as a percentage of left ventricular mass by cardiac MRI at 10 to 12 weeks, with the primary analysis in patients with TIMI Flow Grade 0 to 1 before percutaneous intervention who received at least 2 doses of MEDI6012. The secondary outcome was change in noncalcified plaque volume on coronary computed tomographic angiography from baseline to 10 to 12 weeks with the primary analysis in patients who received all 6 doses of MEDI6012. RESULTS: A total of 593 patients were randomly assigned. Patients were a median of 62 years old, 77.9% male, and 95.8% statin naive. Median time from symptom onset to randomization was 146 (interquartile range [IQR], 103-221) minutes and from hospitalization to randomization was 12.7 (IQR, 6.6-24.0) minutes, and the first dose of drug was administered a median of 8 (IQR, 3-13) minutes before percutaneous intervention. The index myocardial infarction was anterior in 69.6% and TIMI Flow Grade 0 to 1 in 65.1% of patients. At 12 weeks, infarct size did not differ between treatment groups (MEDI6012: 9.71%, IQR 4.79-16.38; placebo: 10.48%, [IQR, 4.92-16.61], 1-sided P=0.79. There was also no difference in noncalcified plaque volume (geometric mean ratio, 0.96 [95% CI, NA-1.10], 1-sided P=0.30). There was no significant difference in treatment emergent serious adverse events. CONCLUSIONS: Administration of MEDI6012 in patients with acute ST-segment-elevation myocardial infarction did not result in a significant reduction in infarct size or noncalcified plaque volume at 12 weeks. MEDI6012 was well tolerated with no excess in overall serious adverse events. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03578809.

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

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.

LCAT protects against Lipoprotein-X formation in a murine model of drug-induced intrahepatic cholestasis.

Familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD) is a rare genetic disease characterized by low HDL-C levels, low plasma cholesterol esterification, and the formation of Lipoprotein-X (Lp-X), an abnormal cholesterol-rich lipoprotein particle. LCAT deficiency causes corneal opacities, normochromic normocytic anemia, and progressive renal disease due to Lp-X deposition in the glomeruli. Recombinant LCAT is being investigated as a potential therapy for this disorder. Several hepatic disorders, namely primary biliary cirrhosis, primary sclerosing cholangitis, cholestatic liver disease, and chronic alcoholism also develop Lp-X, which may contribute to the complications of these disorders. We aimed to test the hypothesis that an increase in plasma LCAT could prevent the formation of Lp-X in other diseases besides FLD. We generated a murine model of intrahepatic cholestasis in LCAT-deficient (KO), wild type (WT), and LCAT-transgenic (Tg) mice by gavaging mice with alpha-naphthylisothiocyanate (ANIT), a drug well known to induce intrahepatic cholestasis. Three days after the treatment, all mice developed hyperbilirubinemia and elevated liver function markers (ALT, AST, Alkaline Phosphatase). The presence of high levels of LCAT in the LCAT-Tg mice, however, prevented the formation of Lp-X and other plasma lipid abnormalities in WT and LCAT-KO mice. In addition, we demonstrated that multiple injections of recombinant human LCAT can prevent significant accumulation of Lp-X after ANIT treatment in WT mice. In summary, LCAT can protect against the formation of Lp-X in a murine model of cholestasis and thus recombinant LCAT could be a potential therapy to prevent the formation of Lp-X in other diseases besides FLD.

Familial lecithin:cholesterol acyltransferase deficiency: First-in-human treatment with enzyme replacement.

BACKGROUND: Humans with familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD) have extremely low or undetectable high-density lipoprotein cholesterol (HDL-C) levels and by early adulthood develop many manifestations of the disorder, including corneal opacities, anemia, and renal disease. OBJECTIVE: To determine if infusions of recombinant human LCAT (rhLCAT) could reverse the anemia, halt progression of renal disease, and normalize HDL in FLD. METHODS: rhLCAT (ACP-501) was infused intravenously over 1 hour on 3 occasions in a dose optimization phase (0.3, 3.0, and 9.0 mg/kg), then 3.0 or 9.0 mg/kg every 1 to 2 weeks for 7 months in a maintenance phase. Plasma lipoproteins, lipids, LCAT levels, and several measures of renal function and other clinical labs were monitored. RESULTS: LCAT concentration peaked at the end of each infusion and decreased to near baseline over 7 days. Renal function generally stabilized or improved and the anemia improved. After infusion, HDL-C rapidly increased, peaking near normal in 8 to 12 hours; analysis of HDL particles by various methods all revealed rapid sequential disappearance of preß-HDL and small α-4 HDL and appearance of normal α-HDL. Low-density lipoprotein cholesterol increased more slowly than HDL-C. Of note, triglyceride routinely decreased after meals after infusion, in contrast to the usual postprandial increase in the absence of rhLCAT infusion. CONCLUSIONS: rhLCAT infusions were well tolerated in this first-in-human study in FLD; the anemia improved, as did most parameters related to renal function in spite of advanced disease. Plasma lipids transiently normalized, and there was rapid sequential conversion of small preß-HDL particles to mature spherical α-HDL particles.

HDL-targeted therapies: progress, failures and future.

Since the discovery in the 1970s that plasma levels of high-density lipoprotein cholesterol (HDL-C) are inversely associated with cardiovascular outcome, it has been postulated that HDL is anti-atherogenic and that increasing HDL-C levels is a promising therapeutic strategy. However, the recent failure of three orally active, HDL-C-raising agents has introduced considerable controversy, prompting the question of whether increasing the cholesterol cargo of HDL in a non-selective manner is an effective pharmacological approach for the translation of its atheroprotective and vasculoprotective activities. The interrelationships between HDL-C concentration, HDL particle number and levels of diverse HDL particle subpopulations of defined composition are complex, as are their relationships with reverse cholesterol transport and other anti-atherogenic functions. Such complexity highlights the incompleteness of our understanding of the biology of HDL particles. This article examines the HDL hypothesis in molecular and mechanistic terms, focusing on features that have been addressed, those that remain to be tested, and potential new targets for future pharmacological interventions.

Lipoprotein subfractions highly associated with renal damage in familial lecithin:cholesterol acyltransferase deficiency.

OBJECTIVE: In familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD), deposition of abnormal lipoproteins in the renal stroma ultimately leads to renal failure. However, fish-eye disease (FED) does not lead to renal damage although the causative mutations for both FLD and FED lie within the same LCAT gene. This study was performed to identify the lipoproteins important for the development of renal failure in genetically diagnosed FLD in comparison with FED, using high-performance liquid chromatography with a gel filtration column. APPROACH AND RESULTS: Lipoprotein profiles of 9 patients with LCAT deficiency were examined. Four lipoprotein fractions specific to both FLD and FED were identified: (1) large lipoproteins (>80 nm), (2) lipoproteins corresponding to large low-density lipoprotein (LDL), (3) lipoproteins corresponding to small LDL to large high-density lipoprotein, and (4) to small high-density lipoprotein. Contents of cholesteryl ester and triglyceride of the large LDL in FLD (below detection limit and 45.8±3.8%) and FED (20.7±6.4% and 28.0±6.5%) were significantly different, respectively. On in vitro incubation with recombinant LCAT, content of cholesteryl ester in the large LDL in FLD, but not in FED, was significantly increased (to 4.2±1.4%), whereas dysfunctional high-density lipoprotein was diminished in both FLD and FED. CONCLUSIONS: Our novel analytic approach using high-performance liquid chromatography with a gel filtration column identified large LDL and high-density lipoprotein with a composition specific to FLD, but not to FED. The abnormal lipoproteins were sensitive to treatment with recombinant LCAT and thus may play a causal role in the renal pathology of FLD.

Lecithin cholesterol acyltransferase: an anti- or pro-atherogenic factor?

Lecithin cholesterol acyl transferase (LCAT) is a plasma enzyme that esterifies cholesterol and raises high-density lipoprotein cholesterol, but its role in atherosclerosis is not clearly established. Studies of various animal models have yielded conflicting results, but studies done in rabbits and non-human primates, which more closely simulate human lipoprotein metabolism, indicate that LCAT is likely atheroprotective. Although suggestive, there are also no biomarker studies that mechanistically link LCAT with cardiovascular disease. Imaging studies of patients with LCAT deficiency have also not yielded a clear answer to the role of LCAT in atherosclerosis. Recombinant LCAT, however, is currently being developed as a therapeutic product for enzyme replacement therapy of patients with genetic disorders of LCAT for the prevention and/or treatment of renal disease, but it may also have value for the treatment of acute coronary syndrome.

Transdermoterapia por electroporación en la lipólisis abdominal / Transdermotherapy by electroporation in abdominal lipolysis

Este estudio presenta los efectos conseguidos por la electroporación en la lipólisis abdominal utilizando la vehiculación de la fosfatidilcolina (fosfolípido que facilita la absorción de las grasas). Se llevó a cabo en 10 mujeres voluntarias, nulíparas, sedentarias, con una edad media de 25,10 años e índice de masa corporal entre 18,5 y 25 kg/m2. Recibieron 15 sesiones de tratamiento fisioterápico, constando esta de una aplicación tópica de fosfatidilcolina al 10% liposomada en el abdomen con electroporación. La técnica consistió en colocar el transductor del equipo en la pared abdominal emitiendo ondas electromagnéticas con un voltaje de 500 mV y una frecuencia de 50 Hz durante 30 minutos. Este tratamiento alcanzó una reducción del tejido adiposo subcutáneo de la pared abdominal, comprobada por medida perimétrica del abdomen, medida del pliegue cutáneo infraumbilical y por ultrasonografía. En la perimetría, la reducción media fue de 4,75 cm, en la plicometría de 2,43 mm y la ultrasonografía demostró una disminución del grosor del tejido adiposo que pasó de una media de 2,21 cm a 1,65 cm. Sin embargo, no se halló ninguna reducción ponderal significativa, aunque la disminución presentada en los tres métodos de evaluación sugiere que la utilización de la fosfatidilcolina con la electroporación puede desencadenar efectos lipolíticos(AU)

The present study presents the effects achieved with electroporation in abdominallipolysis using vehiculization of phosphatidylcholine (phospholipide that facilitates fatabsorption). The study was conducted in 10 voluntary women, nulliparous, sedentary women, with a mean age of 25.10 years and body mass index between 18.5 and 25 kg/m2.They were administered 15 sessions of physiotherapy, this being made up of a topicalapplication of 10% liposomal phosphatidylcholine in the abdomen with electroporation.The technique consisted in placing the equipment transductor on the abdominal wall,emitting electromagnetic waves with a 500mV voltage and 50 Hz frequency for 30 minutes.This treatment achieved a reduction of the subcutaneous adipose tissue of the abdominalwall, verified by perimetric measurement of the abdomen, measurement of infraumbilicalskin fold and by ultrasound. In the perimetry, the mean reduction was 4.75 cm, in theplicometry 2.43mm and the ultrasonograph showed a decrease of adipose tissue thicknessthat went from a mean of 2.21 cm to 1.65 cm. However, no significant weight reduction wasfound, although the decrease found in the three evaluation methods suggests that the useof phosphatidylcholine with electroporation may precipitate lipolitic effects(AU)

Colestasis intrahepática familiar progresiva tip 3. Defecto de MDR3 / Progressive familial intrahepatic cholestasis type 3. An MDR3 defect

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Characterization of lecithin:cholesterol acyltransferase expressed in a human lung cell line.

Lecithin:cholesterol acyltransferase (LCAT) is a key enzyme for the transfer of mammalian cholesterol from peripheral tissues to the liver. In patients deficient in LCAT, serum cholesterol levels rise and can lead to corneal opacity, proteinuria, anemia, and kidney failure. As early as 1968, relatively low volume transfusion of normal plasma was shown to temporarily correct the abnormal lipoprotein profiles in LCAT-deficient patients. However, despite the cloning, study, and extensive expression of LCAT in mammalian cell lines, there is still no viable, clinical therapy for LCAT deficiency. The current study was initiated to provide a source of recombinant human LCAT for enzyme replacement therapy. Accordingly, human LCAT has been cloned and expressed for the first time in a human cell line. The recombinant LCAT secreted by these cells was purified by phenyl-Sepharose chromatography, analyzed to determine the nature of its glycosylation, and tested for its enzymatic properties. The activity and basic kinetic parameters for the enzyme were determined using both a fluorescent water-soluble substrate and a macromolecular (proteoliposome) substrate. The enzymatic properties and the carbohydrate components of the recombinant LCAT were all sufficiently similar to those of the circulating human plasma enzyme, suggesting that this source of LCAT may be appropriate for use in some form of enzyme replacement therapy.