RESUMO
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.
Assuntos
Deficiência da Lecitina Colesterol Aciltransferase/tratamento farmacológico , Fosfatidilcolina-Esterol O-Aciltransferase/uso terapêutico , Anemia/complicações , HDL-Colesterol/sangue , Progressão da Doença , Testes Hematológicos , Humanos , Rim/efeitos dos fármacos , Deficiência da Lecitina Colesterol Aciltransferase/sangue , Deficiência da Lecitina Colesterol Aciltransferase/complicações , Deficiência da Lecitina Colesterol Aciltransferase/enzimologia , Masculino , Pessoa de Meia-Idade , Fosfatidilcolina-Esterol O-Aciltransferase/efeitos adversos , Fosfatidilcolina-Esterol O-Aciltransferase/farmacocinética , Fosfatidilcolina-Esterol O-Aciltransferase/farmacologia , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , SegurançaRESUMO
RATIONALE: Low high-density lipoprotein-cholesterol (HDL-C) in patients with coronary heart disease (CHD) may be caused by rate-limiting amounts of lecithin:cholesterol acyltransferase (LCAT). Raising LCAT may be beneficial for CHD, as well as for familial LCAT deficiency, a rare disorder of low HDL-C. OBJECTIVE: To determine safety and tolerability of recombinant human LCAT infusion in subjects with stable CHD and low HDL-C and its effect on plasma lipoproteins. METHODS AND RESULTS: A phase 1b, open-label, single-dose escalation study was conducted to evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics of recombinant human LCAT (ACP-501). Four cohorts with stable CHD and low HDL-C were dosed (0.9, 3.0, 9.0, and 13.5 mg/kg, single 1-hour infusions) and followed up for 28 days. ACP-501 was well tolerated, and there were no serious adverse events. Plasma LCAT concentrations were dose-proportional, increased rapidly, and declined with an apparent terminal half-life of 42 hours. The 0.9-mg/kg dose did not significantly change HDL-C; however, 6 hours after doses of 3.0, 9.0, and 13.5 mg/kg, HDL-C was elevated by 6%, 36%, and 42%, respectively, and remained above baseline ≤4 days. Plasma cholesteryl esters followed a similar time course as HDL-C. ACP-501 infusion rapidly decreased small- and intermediate-sized HDL, whereas large HDL increased. Pre-ß-HDL also rapidly decreased and was undetectable ≤12 hours post ACP-501 infusion. CONCLUSIONS: ACP-501 has an acceptable safety profile after a single intravenous infusion. Lipid and lipoprotein changes indicate that recombinant human LCAT favorably alters HDL metabolism and support recombinant human LCAT use in future clinical trials in CHD and familial LCAT deficiency patients. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01554800.
Assuntos
Fosfatidilcolina-Esterol O-Aciltransferase/administração & dosagem , Fosfatidilcolina-Esterol O-Aciltransferase/sangue , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Relação Dose-Resposta a Droga , Exantema/induzido quimicamente , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Fosfatidilcolina-Esterol O-Aciltransferase/efeitos adversos , Proteínas Recombinantes/efeitos adversosRESUMO
PURPOSE OF REVIEW: New therapeutic strategies are needed for the rapid stabilization of acute coronary syndrome (ACS) patients by treating nonculprit lesions. Reconstituted HDL (rHDL), which is apoA-I combined with phospholipids, is currently being tested in clinical trials for this purpose and is the subject of this review. RECENT FINDINGS: At least four different formulations (SRC-rHDL, CSL-111, CSL-112 and ETC-216) have been tested in clinical trials. The various rHDL preparations have been shown to be effective in the rapid mobilization of excess cholesterol from cells and in regressing atherosclerotic plaques in animal models. Two of the rHDL agents, namely ETC-216 and CSL-111, have been shown to be effective after only a few treatments in reducing plaque volume in ACS patients, as assessed by intravascular ultrasound, but no clinical trials assessing clinical endpoints have yet been completed. SUMMARY: rHDL is a promising new potential therapy for ACS patients, but much work remains to be done, and there are many unresolved questions. Progress in developing rHDL into a therapy will depend on improving our understanding of their mechanism of action, determining the optimum formulation and delivery and how to monitor rHDL therapy.
Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Lipoproteínas HDL/química , Lipoproteínas HDL/uso terapêutico , Animais , Apolipoproteína A-I/metabolismo , Química Farmacêutica , Humanos , Lipoproteínas HDL/metabolismoRESUMO
Lecithin cholesterol acyl transferase (LCAT) deficiency is associated with low high-density lipoprotein (HDL) and the presence of an abnormal lipoprotein called lipoprotein X (Lp-X) that contributes to end-stage renal disease. We examined the possibility of using LCAT an as enzyme replacement therapy agent by testing the infusion of human recombinant (r)LCAT into several mouse models of LCAT deficiency. Infusion of plasma from human LCAT transgenic mice into LCAT-knockout (KO) mice rapidly increased HDL-cholesterol (C) and lowered cholesterol in fractions containing very-low-density lipoprotein (VLDL) and Lp-X. rLCAT was produced in a stably transfected human embryonic kidney 293f cell line and purified to homogeneity, with a specific activity of 1850 nmol/mg/h. Infusion of rLCAT intravenously, subcutaneously, or intramuscularly into human apoA-I transgenic mice showed a nearly identical effect in increasing HDL-C approximately 2-fold. When rLCAT was intravenously injected into LCAT-KO mice, it showed a similar effect as plasma from human LCAT transgenic mice in correcting the abnormal lipoprotein profile, but it had a considerably shorter half-life of approximately 1.23 ± 0.63 versus 8.29 ± 1.82 h for the plasma infusion. rLCAT intravenously injected in LCAT-KO mice crossed with human apolipoprotein (apo)A-I transgenic mice had a half-life of 7.39 ± 2.1 h and increased HDL-C more than 8-fold. rLCAT treatment of LCAT-KO mice was found to increase cholesterol efflux to HDL isolated from mice when added to cells transfected with either ATP-binding cassette (ABC) transporter A1 or ABCG1. In summary, rLCAT treatment rapidly restored the normal lipoprotein phenotype in LCAT-KO mice and increased cholesterol efflux, suggesting the possibility of using rLCAT as an enzyme replacement therapy agent for LCAT deficiency.
Assuntos
Lipoproteínas/metabolismo , Fosfatidilcolina-Esterol O-Aciltransferase/farmacologia , Animais , Apolipoproteínas E/metabolismo , Colesterol/metabolismo , Ésteres do Colesterol/metabolismo , Cricetinae , Humanos , Infusões Intravenosas , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipoproteínas VLDL/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosfatidilcolina-Esterol O-Aciltransferase/administração & dosagem , Fosfatidilcolina-Esterol O-Aciltransferase/genética , Proteínas RecombinantesAssuntos
Hipolipemiantes/farmacologia , Animais , Anticolesterolemiantes/farmacologia , Anticolesterolemiantes/uso terapêutico , Apolipoproteína A-I/antagonistas & inibidores , Azetidinas/farmacologia , Azetidinas/uso terapêutico , Combinação de Medicamentos , Indústria Farmacêutica/tendências , Ezetimiba , Humanos , Hipolipemiantes/uso terapêutico , Oligonucleotídeos/farmacologia , Oligonucleotídeos/uso terapêutico , Estados Unidos , United States Food and Drug AdministrationRESUMO
A series of long (11-15) hydrocarbon chain diols and diacids with various central functional groups and terminal gem-dimethyl or -methyl/aryl substituents was synthesized and evaluated in both in vivo and in vitro assays for its potential to favorably alter lipid disorders including metabolic syndrome. Compounds were assessed for their effects on the de novo incorporation of radiolabeled acetate into lipids in primary cultures of rat hepatocytes, as well as for their effects on lipid and glycemic variables in obese female Zucker fatty rats, Crl:(ZUC)-faBR. The most active compounds were hydroxyl-substituted symmetrical diacids and diols with a 13-atom chain and terminal gem-dimethyl substituents. Furthermore, biological activity was enhanced by central substitution with O, C=O, S, S=O compared to the methylene analogues and was diminished for compounds with central functional groups such as carbamate, ester, urea, acetylmethylene, and hydroxymethylene.
Assuntos
Álcoois/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Ácidos Dicarboxílicos/uso terapêutico , Hidrocarbonetos/uso terapêutico , Hiperlipidemias/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Administração Oral , Álcoois/administração & dosagem , Álcoois/síntese química , Animais , Diabetes Mellitus Experimental/metabolismo , Ácidos Dicarboxílicos/administração & dosagem , Ácidos Dicarboxílicos/síntese química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Tolerância a Medicamentos , Feminino , Hepatócitos/efeitos dos fármacos , Hidrocarbonetos/administração & dosagem , Hidrocarbonetos/síntese química , Hiperlipidemias/metabolismo , Hipolipemiantes/administração & dosagem , Hipolipemiantes/síntese química , Técnicas In Vitro , Lipídeos/antagonistas & inibidores , Lipídeos/biossíntese , Estrutura Molecular , Ratos , Ratos Zucker , Relação Estrutura-Atividade , Fatores de TempoRESUMO
A series of cycloalkyl-substituted oxo-alkanedicarboxylic acids have been prepared by the TosMIC methodology departing from haloalkyl-substituted cycloalkylcarboxylic esters. cyclopropyl derivatives showed IC(50) activity in the 0.3-1.0 microM range on the de novo incorporation of radiolabeled acetate into lipids in primary cultures of rat hepatocytes, and they showed lipid-regulating properties when tested in vivo in female obese Zucker fatty rats.
Assuntos
Ácidos Dicarboxílicos/farmacologia , Lipídeos/sangue , Lipoproteínas/sangue , Animais , Células Cultivadas , Ácidos Dicarboxílicos/química , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Espectroscopia de Ressonância Magnética , Masculino , Espectrometria de Massas , Ratos , Ratos Sprague-DawleyAssuntos
Angina Instável/tratamento farmacológico , Infarto do Miocárdio/tratamento farmacológico , Doença Aguda , Angina Instável/sangue , Angina Instável/enzimologia , Animais , Anticolesterolemiantes/uso terapêutico , Apolipoproteína A-I/uso terapêutico , LDL-Colesterol/sangue , Vasos Coronários/patologia , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Infarto do Miocárdio/sangue , Infarto do Miocárdio/enzimologia , SíndromeRESUMO
LCAT is a key enzyme of reverse cholesterol transport that is essential to maintain HDL-mediated lipid transport and cholesterol homeostasis. Alterations in LCAT expression have a profound effect on plasma HDL cholesterol concentrations. Previously LCAT mRNA and activity were shown to be regulated by several inflammatory cytokines, including the pleiotrophic cytokine interleukin-6 (IL-6). A series of full-length and sequential deletion LCAT promoter constructs were used to determine whether inflammatory stimuli affect LCAT transcription and to further identify functional, cytokine-responsive promoter regions that mediate this response. Using transfected HepG2 cells, results indicate that treatment with IL-6 induced a 2.5-fold activation of full-length LCAT promoter activity. A minimal (-1514 bp to -1508 bp) IL-6 response element with high sequence homology to the signal transducer and activator of transcription (STAT) family member, STAT3, was mapped within the distal promoter and shown to be sufficient to mediate the IL-6 response. Further, overexpression of STAT3 significantly enhanced the effect of IL-6 on LCAT promoter activity. These data suggest that the IL-6 responsive transcription factor, STAT3, contributes to LCAT transcriptional regulation. The elucidation of distinct biochemical signaling pathways associated with inflammation may provide new insight into transcriptional regulation of genes involved in lipid metabolism.
Assuntos
Interleucina-6/metabolismo , Fosfatidilcolina-Esterol O-Aciltransferase/genética , Regiões Promotoras Genéticas , Elementos de Resposta , Sítios de Ligação , Proteínas de Ligação a DNA/metabolismo , Humanos , Interleucina-1/metabolismo , Fator de Transcrição STAT3 , Transativadores/metabolismo , Regulação para CimaRESUMO
Although pharmacologic intervention to treat atherosclerosis originally focused on lowering LDL-cholesterol levels as a therapeutic target, a number of intervention trials have also highlighted the powerful effect of elevating HDL-cholesterol levels to reduce cardiovascular morbidity and mortality. Although the mechanism(s) by which HDL beneficially alters the atherosclerotic disease process is (are) still unknown, it is presumed that high levels of HDL facilitate the efflux of cholesterol from the arterial wall, thereby enhancing the transport of cholesterol and other lipids from arteries back to the liver for biliary excretion as fecal sterols and bile acids. It has therefore been hypothesized that through a rapid facilitation of HDL mediated cholesterol efflux from arteries by infusion of synthetic apolipoprotein A-I (apoA-I)/phospholipid (A-I/PL) complexes, HDL therapy could have an acute therapeutic application to treat cardiovascular disease at the site of action, namely the vulnerable, unstable atherosclerotic plaque. Single high dose infusions and repeated injections of lower doses of apoA-I variants or mimetics complexed to phospholipids have produced remarkable effects on the progression and regression of atherosclerosis in animal models. The positive results of these preclinical experiments have compelled researchers to perform exploratory studies in human subjects in which reconstituted HDL and synthetic A-I/PL complexes are infused through a peripheral vein. These clinical studies are testing the hypothesis and the potential use of synthetic HDL as a new treatment modality for acute coronary syndromes. Given that there is an unmet medical need for new and more effective therapies to elevate HDL-cholesterol levels and improve HDL function, a historical review, update and discussion of the preclinical and clinical studies which support the use of HDL therapy for reducing cardiovascular morbidity and mortality is warranted.