Acid Lipase Deficiency Research Articles

Clinical experience with orphan drugs for rare metabolic diseases

IntroductionInborn errors of metabolism are a highly heterogeneous group of orphan diseases. Diet therapy and enzyme and coenzyme replacement are the most frequently used treatment. There are few patients and published studies about inborn errors of metabolism. The main objective of this study was to describe the effectiveness of orphan drugs in inborn errors of metabolism in paediatric patients. Material and methodsRetrospective descriptive study of 24 months on patients diagnosed with inborn errors of metabolism during childhood and who attended the pharmacy clinic or Day-Care Unit of a 630-bed general hospital. ResultsThe study included 15 patients with a median age of 17.8 years and were treated with nine different drugs: sapropterin, sodium phenylbutyrate, miglustat, velaglucerase, sebelipase, idursulfase, 5-hydroxytryptophan, succinate, and riboflavin. Seven different inborn errors of metabolism were observed: phenylketonuria, defects of the urea cycle, Gaucher, Nieman-Pick, Hunter’s disease, along with acid lipase deficiency, and mitochondrial diseases. Orphan drugs used for the treatment of inborn errors of metabolism accounted for 1.3% of hospital drug costs. Some orphan drugs achieved asymptomatic patients, but others just produced a modest symptomatic improvement. Most patients showed good tolerance to the treatment. ConclusionsOrphan drugs used in inborn errors of metabolism had an easy to manage toxicity profile, with many disparities in effectiveness. These drugs have a high economic impact. The cost-effectiveness ratio for orphan drugs is a controversial issue due to their high cost and the inconclusive clinical evidence.

Experiencia clínica con medicamentos huérfanos para enfermedades raras metabólicas

IntroductionInborn errors of metabolism are a highly heterogeneous group of orphan diseases. Diet therapy and enzyme and coenzyme replacement are the most frequently used treatment. There are few patients and published studies about inborn errors of metabolism. The main objective of this study was to describe the effectiveness of orphan drugs in inborn errors of metabolism in paediatric patients. Material and MethodsRetrospective descriptive study of 24 months on patients diagnosed with inborn errors of metabolism during childhood and who attended the pharmacy clinic or Day-Care Unit of a 630-bed general hospital. ResultsThe study included 15 patients with a median age of 17.8 years and were treated with nine different drugs: sapropterin, sodium phenylbutyrate, miglustat, velaglucerase, sebelipase, idursulfase, 5-hydroxytryptophan, succinate, and riboflavin. Nine different inborn errors of metabolism were observed: phenylketonuria, defects of the urea cycle, Gaucher, Nieman-Pick, Hunter's disease, along with acid lipase deficiency, and mitochondrial diseases. Orphan drugs used for the treatment of inborn errors of metabolism accounted for 1.3% of hospital drug costs. Some orphan drugs achieved asymptomatic patients, but others just produced a modest symptomatic improvement. Most patients showed good tolerance to the treatment. ConclusionsOrphan drugs used in inborn errors of metabolism had an easy to manage toxicity profile, with many disparities in effectiveness. These drugs have a high economic impact. The cost-effectiveness ratio for orphan drugs is a controversial issue due to their high cost and the inconclusive clinical evidence.

Abstract A11: Myeloid-derived suppressor cells suppress immune surveillance and stimulate cancer cell proliferation/metastasis through activation of mTOR pathway in lal-/- mice

Abstract Inflammation critically contributes to cancer metastasis, in which myeloid-derived suppressor cells (MDSCs) are an important participant. Although MDSCs are known to suppress immune surveillance, their roles in directly stimulating cancer cell proliferation and metastasis currently remain unclear. MDSCs development and homeostasis is controlled by lysosomal acid lipase (LAL), a critical enzyme in the metabolic signaling pathway that hydrolyzes cholesteryl esters (CE) and triglycerides (TG) in lysosomes. Lysosomal acid lipase (LAL) deficiency causes systemic expansion and infiltration of MDSCs in multiple organs. LAL-deficient (lal-/-) MDSCs arise from dysregulated production of progenitor cells in the bone marrow. In humans, increased CD14+CD16+ and CD14+CD33+ MDSC subsets have been reported with heterozygote carriers of LAL mutations. Patients with mutations in the LAL gene has been reported to be associated with carcinogenesis. In the LAL-deficient (lal-/-) mouse model, melanoma metastasized massively in allogeneic lal-/- mice, which was suppressed in allogeneic lal+/+ mice due to immune rejection. Here we report for the first time that MDSCs isolated from lal-/- mice directly stimulated B16 melanoma cell proliferation in vitro, and growth and metastasis in vivo. Cytokines i.e., IL-1β and TNFα from MDSCs are required for B16 melanoma cell proliferative function in vitro. Myeloid-specific expression of human LAL (hLAL) in lal-/- mice rescues these malignant phenotypes in vitro and in vivo. The tumor-promoting function of lal-/- MDSCs is mediated, at least in part, through over-activation of the mammalian target of rapamycin (mTOR) pathway. mTOR is a serine/threonine protein kinase that regulates cell growth, proliferation, migration, survival, protein synthesis, and transcription in response to growth factors and mitogens. mTOR is the catalytic subunit of two distinctive complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Unique accessory proteins, regulatory-associated protein of mTOR (RAPTOR), and rapamycin-insensitive companion of mTOR (RICTOR) define the TORC1 and TORC2 complexes, respectively. Affymetrix GeneChip microarray analysis and Ingenuity Pathway Analysis of gene transcripts revealed up-regulation of multiple genes in the mTOR signaling pathway in lal-/- MDSCs. We have shown that inhibition of mTOR in lal-/- MDSCs increased apoptosis, decreased ATP synthesis, decreased ROS production, and recovered impairment of mitochondrial membrane potential. As a result, lal-/- MDSCs reversed the increased cell proliferation, corrected enhanced lal-/- MDSCs development from lineage negative progenitor cells, and reduced systemic MDSC expansion. More importantly, knockdown of mTOR, Raptor or Rictor in lal-/- MDSCs reversed the immune suppression on T cell proliferation and function, as well as suppressed their stimulation on proliferation of cancer cells (including B16 melanoma, LLC and Tramp-C2 cancer cells). Our results indicate that LAL plays a critical role in regulating MDSCs through modulation of the mTOR pathway. MDSCs possess dual functions to overcome immune rejection and facilitate cancer metastasis: 1) suppress immune surveillance, and 2) stimulate cancer cell proliferation, growth, and metastasis. Grant support: This work was supported by National Institutes of Health Grants CA138759, CA152099 (to C. Y.) and HL087001 (to H. D.). Citation Format: Hong Du, Ting Zhao, Xinchun Ding, Katlin Walls, Cong Yan. Myeloid-derived suppressor cells suppress immune surveillance and stimulate cancer cell proliferation/metastasis through activation of mTOR pathway in lal-/- mice. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A11.

Sebelipase Alfa for Treatment of Lysosomal Acid Lipase Deficiency

Lysosomal acid lipase deficiency — an autosomal recessive storage disease that commonly manifests as elevated liver enzymes, dyslipidemia, hepatomegaly, and liver fibrosis — is an underappreciated cause of cirrhosis in both children and adults. In a manufacturer-sponsored, multicenter, phase III, double-blind trial, researchers evaluated the efficacy of sebelipase alfa enzyme replacement in patients aged ≥4 years with this disorder. Participants were randomized to …

Effect of time of initiating enzyme replacement therapy on immune dysfunction in patients with Gaucher disease

CO RR EC TE D P RO OF a test (Filipin test) performed in living fibroblasts obtained from a skin biopsy, with the positive and inconclusive results usually having to be further investigated by molecular analysis of the NPC1 and NPC2 genes (30 exons in total). Assays for other lysosomal enzymes may also be performed along the investigation, as needed. Chitotriosidase (CT) activity is increased in most NPC patients, but this test is not very specific as high activities are also observed in Gaucher, Niemann–Pick types A/B, acid lipase deficiency and several other conditions. The analysis of oxysterols has recently been proposed as a potential method to identify NPC patients, especially cholestan-3β,5α,6β-triol (triol). Our group coordinates a large network of Brazilian services which investigates patients at risk of presenting NPC. Samples from high-risk patients investigated by the measurement of CT activity (plasma) and by the Filipin test (cultured fibroblasts), were also submitted to the tandem mass spectrometry assay of triol (plasma). In 21 high-risk patients investigated we found that all 3 cases with positive Filipin test had also increased triol levels (with CT also increased). In 9 patients in whom Filipin test resulted inconclusive, 1 had increased triol levels, with CT activity also increased, being potentially a variant NPC case (enzyme assays ruled out another LSD, and molecular analysis for NPC1 and NPC2 is in progress). In 9 cases with negative Filipin test, triol was normal in all except one, who had also increased CT levels and was later diagnosed with Niemann–Pick disease type A. These preliminary results, which should be expanded and completed with the results of the molecular analysis of the NPC1 and NPC2 genes, suggest that oxysterol measurement, although not specific, is a noninvasive, fast and sensitive method that could play a role in the screening of NPC disease.

Co-localization of macrophage aggregation and fibrosis in a rat model of lysosomal acid lipase (LAL) deficiency and the effects of enzyme replacement with SBC-102

Co-localization of macrophage aggregation and fibrosis in a rat model of lysosomal acid lipase (LAL) deficiency and the effects of enzyme replacement with SBC-102

“You can't always get what you want”: Filipin staining unmasking lysosomal acid lipase (LAL) deficiency in a young child

“You can't always get what you want”: Filipin staining unmasking lysosomal acid lipase (LAL) deficiency in a young child

Lactosylceramide in lysosomal storage disorders. A comparative immunohistochemical and biochemical study

Immunohistochemical studies of the presence of lactosylceramide (LacCer) in lysosomal storage disorders (LSDs) were done using anti-LacCer monoclonal antibody of the CDw 17 type (clone MG-2). No sign of an association between LacCer and the lysosomal system in normal cells was observed, except for histiocytes active in phagocytosis. A comparative study of a group of LSDs showed a general tendency for LacCer to increase in storage cells in Niemann-Pick disease type C (NPC), and types A and B, GM1 gangliosidosis, acid lipase deficiency, glycogen storage disease type II and mucopolysaccharidoses. LacCer accumulated in storage cells despite normal activity of relevant lysosomal degrading enzymes. The accumulation of LacCer displayed variability within storage cell populations, and was mostly expressed in neurons in NPC. An absence of the increase in LacCer in storage cells above control levels was seen in neuronal ceroid lipofuscinoses (neurons and cardiocytes) and in Fabry disease. Gaucher and Krabbe cells showed significantly lower levels, or even the absence, of LacCer compared with control macrophages. Results of immunohistochemistry were corroborated by semiquantitative lipid thin-layer chromatography (TLC). It is suggested that different associations of LacCer with the lysosomal storage process may reflect differences in glycosphingolipid turnover induced by the storage-compromised lysosomal/endosomal system.

Cholesterol Ester Storage Disease

SummaryCholesterol ester storage disease (CESD) is infrequent in children. Four new cases in two nonrelated families are presented. Acid lipase deficiency in the leukocytes of the patients and reduced activity (50%) in those of parents were demonstrated. Clinical manifestations varied from neonatal cholestasis to asymptomatic hepatomegaly. Hepatic histology showed lipid vacuoles and cholesterol ester storage in hepatocytes and Kupffer cells. Increased levels of cholesterol and hepatomegaly were the first findings. There is as yet no specific treatment for CESD: however, the early detection of cases would make possible the timely control of complications.

Cholesterol Ester Storage Disease

Cholesterol ester storage disease (CESD) is infrequent in children. Four new cases in two nonrelated families are presented. Acid lipase deficiency in the leukocytes of the patients and reduced activity (50%) in those of parents were demonstrated. Clinical manifestations varied from neonatal cholestasis to asymptomatic hepatomegaly. Hepatic histology showed lipid vacuoles and cholesterol ester storage in hepatocytes and Kupffer cells. Increased levels of cholesterol and hepatomegaly were the first findings. There is as yet no specific treatment for CESD; however, the early detection of cases would make possible the timely control of complications.

Cholesterol ester storage disease: Clinical, biochemical, and pathological studies

Of three siblings affected with cholesterol ester storage disease, two died at ages 7 and 9 years, respectively, with hepatic scarring and portal hypertension. Lipid storage was documented in both patients, as were esophageal varices and aortic plaques in the older child. The third affected sibling, followed to 13 years of age, has hepatomegaly, hyperlipidemia, short stature, adrenal calcification, and acid lipase deficiency. Leukocyte extracts demonstrated deficiency of acid lipase in this patient. This autosomal recessive condition may be allelic with Wolman disease with a more malignant course in this family than in most reported cases.

Lipid accumulation and acid lipase deficiency in fibroblasts from a family with Wolman's disease, and their apparent correction in vitro.

Abstract We have previously demonstrated lipid accumulation in fibroblasts cultured from skin biopsies of two children with Wolman's disease. This study was designed to confirm that finding, to measure acid lipase activity of cultured fibroblasts, and to attempt to reduce intracellular accumulation of lipid by a complementation technique. Skin fibroblasts from both patients and their parents showed histochemical evidence of fat accumulation after 3 months in culture. No such change was seen in 7 control subjects. When these cells were assayed for acid lipase activity, 1 child (AD) had much lower levels than the 7 control subjects, while the parents' values were intermediate. No enzyme studies were carried out on the cells from the other child (FD). An autosomal recessive mode of inheritance is postulated. When fat-laden fibroblasts from both patients and the father were exposed for 1 to 2 weeks to media preincubated with normal cells, lipid accumulation demonstrable by fat stains was greatly diminished but returned on withdrawal of the corrective medium.

Reinvestigation of the pathogenesis of familial xanthomatosis through conjoint cytochemical, ultrastructural, and biochemical studies

Autopsy tissues of a patient with Wolman's disease were examined biochemically, cytochemically, and with an electron microscope. In all tissues except brain, lysosomes of the cells of the reticuloendothelial system were filled with droplets of triglycerides and with cholesterol ester crystals. The parenchymal cells of adrenals and liver contained these compounds within large vacuoles which did not appear to be lysosomal in origin but which derived from, or were part of, the smooth and the rough endoplasmic reticulum cisternae. Most lysosomes of parenchymal cells were morphologically normal. Their acid β-glycerophosphatase activity was normal in liver hepatocytes and enhanced in parenchymal cells of the adrenals. These data suggest that an excessive synthesis of lipids rather than a deficiency of lysosomal “acid lipase” is responsible for the disease. However, a partial deficiency in acid lipase was found biochemically in the tissues examined. The apparent contradiction between biochemical and morphological data is discussed by the authors.