Acid Lipase

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Maja Di Rocco - One of the best experts on this subject based on the ideXlab platform.

  • long term substrate reduction therapy with ezetimibe alone or associated with statins in three adult patients with lysosomal Acid Lipase deficiency
    Orphanet Journal of Rare Diseases, 2018
    Co-Authors: Maja Di Rocco, Angela Madeo, Marta Bertamino, Livia Pisciotta, Samuel Bertolini
    Abstract:

    Lysosomal Acid Lipase deficiency is an autosomal recessive metabolic disease with a wide range of severity from Wolman Disease to Cholesterol Ester Storage Disease. Recently enzyme replacement therapy with sebeLipase alpha has been approved by drug agencies for treatment of this lysosomal disease. Ezetimibe is an azetidine derivative which blocks Niemann Pick C1-Like 1 Protein; as its consequence, plasmatic concentration of low density lipoproteins and other apoB-containing lipoproteins, that are the substrate of lysosomal Acid Lipase, are decreased. Furthermore, ezetimibe acts by blocking inflammasome activation which is the cause of liver fibrosis in steatohepatitis and in lysosomal storage diseases. Two patients with Cholesterol Ester Storage Disease were treated with ezetimibe for 9 years and a third patients for 10 years. Treatment was supplemented with low dose of atorvastatin in the first two patients during the last 6 years. All patients showed a significant reduction of alanine aminotransferase, cholesterol and triglyceride. Furthermore, no progression of liver fibrosis was demonstrated. In this observational case series, ezetimibe is effective, safe, and sustainable treatment for lysosomal Acid Lipase deficiency. Further studies are warranted to demonstrate that ezetimibe is an alternative therapy to enzyme replacement therapy.

  • a phase 3 trial of sebeLipase alfa in lysosomal Acid Lipase deficiency
    The New England Journal of Medicine, 2015
    Co-Authors: Barbara K Burton, Patrick Deegan, Manisha Balwani, Francois Feillet, Ivo Baric, Andrew T Burrow, Carmen Camarena Grande, Mahmut Coker, Alejandra Consuelosanchez, Maja Di Rocco
    Abstract:

    BackgroundLysosomal Acid Lipase is an essential lipid-metabolizing enzyme that breaks down endocytosed lipid particles and regulates lipid metabolism. We conducted a phase 3 trial of enzyme-replacement therapy in children and adults with lysosomal Acid Lipase deficiency, an underappreciated cause of cirrhosis and severe dyslipidemia. MethodsIn this multicenter, randomized, double-blind, placebo-controlled study involving 66 patients, we evaluated the safety and effectiveness of enzyme-replacement therapy with sebeLipase alfa (administered intravenously at a dose of 1 mg per kilogram of body weight every other week); the placebo-controlled phase of the study was 20 weeks long and was followed by open-label treatment for all patients. The primary end point was normalization of the alanine aminotransferase level. Secondary end points included additional disease-related efficacy assessments, safety, and side-effect profile. ResultsSubstantial disease burden at baseline included a very high level of low-densit...

Gregory A Grabowski - One of the best experts on this subject based on the ideXlab platform.

  • lysosomal Acid Lipase deficiency expanding differential diagnosis
    Molecular Genetics and Metabolism, 2017
    Co-Authors: Vassili Valayannopoulos, Eugen Mengel, Anais Brassier, Gregory A Grabowski
    Abstract:

    The differential diagnoses for metabolic liver diseases may be challenging in clinical settings, which represents a critical issue for disorders such as lysosomal Acid Lipase deficiency (LAL-D). LAL-D is caused by deficient activity of the LAL enzyme, resulting in the accumulation of cholesteryl esters and triglycerides throughout the body, predominately in the liver, spleen, gastrointestinal tract, and blood vessel walls. LAL-D is a progressive, multi-organ disease with early mortality and significant morbidity characterized by a combination of hepatic dysfunction and dyslipidemia. Evidence suggests LAL-D may be substantially underdiagnosed or misdiagnosed, which is critical given that disease progression can be unpredictable, with liver failure and/or accelerated atherosclerosis potentially contributing to early mortality. However, given the development of a simple diagnostic test and recently approved treatment, LAL-D should be incorporated into the differential diagnosis in relevant clinical settings. LAL-D can be diagnosed using an LAL enzyme-based biochemical test, thereby allowing for active monitoring of patients to detect potential disease complications and consider treatment options including diet, lipid-lowering medication, and treatment with sebeLipase alfa, a recombinant enzyme replacement therapy shown to provide clinical benefit and improve disease-relevant markers in clinical trials. To illustrate the complexity of diagnosing LAL-D, this manuscript will describe the path to diagnosing LAL-D in a series of patient cases in which LAL-D was diagnosed as well as in patients where other diseases, such as Gaucher disease and Niemann-Pick disease, were initially suspected.

  • chemical screen to reduce sterol accumulation in niemann pick c disease cells identifies novel lysosomal Acid Lipase inhibitors
    Biochimica et Biophysica Acta, 2009
    Co-Authors: Anton I Rosenbaum, Hong Du, Gregory A Grabowski, Madalina Rujoi, Amy Huang, Frederick R Maxfield
    Abstract:

    Niemann-Pick C disease (NPC) is a lysosomal storage disorder causing abnormal accumulation of unesterified free cholesterol in lysosomal storage organelles. High content phenotypic microscopy chemical screens in both human and hamster NPC-deficient cells have identified several compounds that partially revert the NPC phenotype. Cell biological and biochemical studies show that several of these molecules inhibit lysosomal Acid Lipase, the enzyme that hydrolyzes LDL-derived triacylglycerol and cholesteryl esters. The effects of reduced lysosomal Acid Lipase activity in lowering cholesterol accumulation in NPC mutant cells were verified by RNAi-mediated knockdown of lysosomal Acid Lipase in NPC1-deficient human fibroblasts. This work demonstrates the utility of phenotypic cellular screens as a means to identify molecular targets for altering a complex process such as intracellular cholesterol trafficking and metabolism.

  • Lysosomal Acid Lipase and atherosclerosis.
    Current Opinion in Lipidology, 2004
    Co-Authors: Hong Du, Gregory A Grabowski
    Abstract:

    PURPOSE OF REVIEW: Atherosclerosis remains the leading cause of death in the developed countries. In addition to lipid-lowering drugs - statins, dietary control, and exercise, new approaches are needed for the treatment and prevention of atherosclerosis. This review will focus on the role(s) of lysosomal Acid Lipase and its use as an enzyme therapy to reduce atherosclerotic lesions in a mouse model and to examine the molecular basis supporting this novel strategy and its mechanism of effect. RECENT FINDINGS: Administration of human lysosomal Acid Lipase via tail vein into mice with atherosclerosis eliminates early aortic and coronary ostial lesions and reduces lesional size in advanced disease. The reduction of advanced lesional area is related to decreases in foamy macrophages, collagen positive areas, and necrotic areas. Compared with sham-treated mice, the human lysosomal Acid Lipase-treated mice also have reduced levels of plasma cholesteryl esters, and reduced levels of hepatic cholesterol and triglycerides. SUMMARY: These studies indicate that administrated lysosomal Acid Lipase affects the atherogenesis by at least two mechanisms: (1) direct targeting of lesional macrophages with resultant decreases in cholesteryl esters and triglyceride in the lysosomes of macrophages in the lesions; (2) systemic effects that mediate the liver to reduce the hepatic cholesteryl ester and triglyceride release, possibly leading to reduced production of VLDL and LDL.

  • Reduction of Atherosclerotic Plaques by Lysosomal Acid Lipase Supplementation
    Arteriosclerosis Thrombosis and Vascular Biology, 2003
    Co-Authors: Hong Du, Susan C. Schiavi, Mark Levine, David P. Witte, Gregory A Grabowski
    Abstract:

    OBJECTIVE: Proof of principle is presented for targeted enzyme supplementation by using lysosomal Acid Lipase to decrease aortic and coronary wall lipid accumulation in a mouse model of atherosclerosis. METHODS AND RESULTS: Mice with LDL receptor deficiency were placed on an atherogenic diet and developed predictable aortic and coronary atheroma. alpha-Mannosyl-terminated human lysosomal Acid Lipase (phLAL) was produced in Pichia pastoris, purified, and administered intravenously to such mice with either early or late lesions. phLAL injections reduced plasma, hepatic, and splenic cholesteryl esters and triglycerides in affected mice. phLAL was detected in hepatic Kupffer cells and in atheromatous foam cells. Repeated enzyme injections were well tolerated, with no obvious adverse effects. In addition, the coronary and aortic atheromatous lesions were (1) eliminated in their early stages and (2) quantitatively and qualitatively reduced in their advanced stages. CONCLUSIONS: These results support the potential utility of lysosomal Acid Lipase supplementation for the treatment of atherosclerosis, a leading cause of mortality and morbidity in Westernized nations.

Samuel Bertolini - One of the best experts on this subject based on the ideXlab platform.

  • long term substrate reduction therapy with ezetimibe alone or associated with statins in three adult patients with lysosomal Acid Lipase deficiency
    Orphanet Journal of Rare Diseases, 2018
    Co-Authors: Maja Di Rocco, Angela Madeo, Marta Bertamino, Livia Pisciotta, Samuel Bertolini
    Abstract:

    Lysosomal Acid Lipase deficiency is an autosomal recessive metabolic disease with a wide range of severity from Wolman Disease to Cholesterol Ester Storage Disease. Recently enzyme replacement therapy with sebeLipase alpha has been approved by drug agencies for treatment of this lysosomal disease. Ezetimibe is an azetidine derivative which blocks Niemann Pick C1-Like 1 Protein; as its consequence, plasmatic concentration of low density lipoproteins and other apoB-containing lipoproteins, that are the substrate of lysosomal Acid Lipase, are decreased. Furthermore, ezetimibe acts by blocking inflammasome activation which is the cause of liver fibrosis in steatohepatitis and in lysosomal storage diseases. Two patients with Cholesterol Ester Storage Disease were treated with ezetimibe for 9 years and a third patients for 10 years. Treatment was supplemented with low dose of atorvastatin in the first two patients during the last 6 years. All patients showed a significant reduction of alanine aminotransferase, cholesterol and triglyceride. Furthermore, no progression of liver fibrosis was demonstrated. In this observational case series, ezetimibe is effective, safe, and sustainable treatment for lysosomal Acid Lipase deficiency. Further studies are warranted to demonstrate that ezetimibe is an alternative therapy to enzyme replacement therapy.

Joep C Defesche - One of the best experts on this subject based on the ideXlab platform.

Michael H Gelb - One of the best experts on this subject based on the ideXlab platform.

  • a case of lysosomal Acid Lipase deficiency confirmed by response to sebeLipase alfa therapy
    Journal of Pediatric Gastroenterology and Nutrition, 2020
    Co-Authors: Joseph Shen, Jessica L Davis, Xinying Hong, Fred H Laningham, Michael H Gelb
    Abstract:

    Lysosomal Acid Lipase (LAL) deficiency, or cholesterol ester storage disease, is a disorder affecting the breakdown of cholesterol esters and triglycerides within lysosomes. Clinical findings include hepatomegaly, hepatic dysfunction, and dyslipidemia, with a wide range of phenotypic variability and age of onset (1-3). The available clinical and molecular information of the patient presented herein was consistent with a diagnosis of LAL deficiency, but her LAL activity assay repeatedly showed normal or borderline low results. Her response to enzyme replacement therapy (4,5) and demonstrable deficiency on a newer specific enzymatic assay (6) ultimately confirmed her diagnosis of LAL deficiency.