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Neal J. Weinreb - One of the best experts on this subject based on the ideXlab platform.
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Gaucher Disease in bone from pathophysiology to practice
Journal of Bone and Mineral Research, 2019Co-Authors: Derralynn Hughes, Ozlem Gokeralpan, Nadia Belmatoug, Pramod K. Mistry, Timothy M Cox, P Mikosch, Francesca Carubbi, Andreas Kindmark, L W Poll, Neal J. WeinrebAbstract:Gaucher Disease (GD) is a rare, genetic lysosomal disorder leading to lipid accumulation and dysfunction in multiple organs. Involvement of the skeleton is one of the most prevalent aspects of GD a ...
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Gaucher Disease progress and ongoing challenges
Molecular Genetics and Metabolism, 2017Co-Authors: Pramod K. Mistry, Neal J. Weinreb, Raphael Schiffmann, Grisel Lopez, Norman W Barton, Ellen SidranskyAbstract:Over the past decades, tremendous progress has been made in the field of Gaucher Disease, the inherited deficiency of the lysosomal enzyme glucocerebrosidase. Many of the colossal achievements took place during the course of the sixty-year tenure of Dr. Roscoe Brady at the National Institutes of Health. These include the recognition of the enzymatic defect involved, the isolation and characterization of the protein, the localization and characterization of the gene and its nearby pseudogene, as well as the identification of the first mutant alleles in patients. The first treatment for Gaucher Disease, enzyme replacement therapy, was conceived of, developed and tested at the Clinical Center of the National Institutes of Health. Advances including recombinant production of the enzyme, the development of mouse models, pioneering gene therapy experiments, high throughput screens of small molecules and the generation of induced pluripotent stem cell models have all helped to catapult research in Gaucher Disease into the twenty-first century. The appreciation that mutations in the glucocerebrosidase gene are an important risk factor for parkinsonism further expands the impact of this work. However, major challenges still remain, some of which are described here, that will provide opportunities, excitement and discovery for the next generations of Gaucher investigators.
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recommendations for the use of eliglustat in the treatment of adults with Gaucher Disease type 1 in the united states
Molecular Genetics and Metabolism, 2016Co-Authors: Manisha Balwani, Ozlem Gokeralpan, Pramod K. Mistry, Priya S. Kishnani, Paige Kaplan, Joel Charrow, Thomas A Burrow, Jeremy N Ruskin, Neal J. WeinrebAbstract:In Gaucher Disease, deficient activity of acid β-glucosidase results in accumulation of its substrates, glucosylceramide and glucosylsphingosine, within the lysosomes of cells primarily in the spleen, liver, bone marrow, and occasionally the lung. The multisystem Disease is predominantly characterized by hepatosplenomegaly, anemia, thrombocytopenia, and skeletal Disease. Enzyme replacement therapy with recombinant human acid β-glucosidase has been the first-line therapy for Gaucher Disease type 1 for more than two decades. Eliglustat, a novel oral substrate reduction therapy, was recently approved in the United States and the European Union as a first-line treatment for adults with Gaucher Disease type 1. Eliglustat inhibits glucosylceramide synthase, thereby decreasing production of the substrate glucosylceramide and reducing its accumulation. Although existing recommendations for the care of patients with Gaucher Disease remain in effect, unique characteristics of eliglustat require additional investigation and monitoring. A panel of physicians with expertise in Gaucher Disease and experience with eliglustat in the clinical trials provide guidance regarding the use of eliglustat, including considerations before starting therapy and monitoring of patients on eliglustat therapy.
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enzyme replacement and substrate reduction therapy for Gaucher Disease
Cochrane Database of Systematic Reviews, 2015Co-Authors: Elad Shemesh, Laura Deroma, Bruno Bembi, Carla E M Hollak, Patrick Deegan, Neal J. WeinrebAbstract:Background Gaucher Disease, a rare disorder, is caused by inherited deficiency of the enzyme glucocerebrosidase. It is unique among the ultra-orphan disorders in that four treatments are currently approved by various regulatory authorities for use in routine clinical practice. Hitherto, because of the relatively few people affected worldwide, many of whom started therapy during a prolonged period when there were essentially no alternatives to imiglucerase, these treatments have not been systematically evaluated in studies such as randomized controlled trials now considered necessary to generate the highest level of clinical evidence. Objectives To summarize all available randomized controlled study data on the efficacy and safety of enzyme replacement therapies and substrate reduction therapy for treating Gaucher Disease. Search methods We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register. Additional searches were conducted on ClinicalTrials.gov for any ongoing studies with potential interim results, and through PubMed. We also searched the reference lists of relevant articles and reviews. Date of last search: 07 August 2014. Selection criteria All randomized and quasi-randomized controlled studies (including open-label studies and cross-over studies) assessing enzyme replacement therapy or substrate reduction therapy, or both, in all types of Gaucher Disease were included. Data collection and analysis Two authors independently assessed the risk of bias in the included studies, and extracted relevant data. Main results Of the 488 studies retrieved by the electronic searches, eight met the inclusion criteria and were analysed (300 participants). Response parameters were restricted to haemoglobin concentration, platelet count, spleen and liver volume and serum biomarkers (chitotriosidase and CCL18). Only one publication reported a 'low risk of bias' score in all parameters assessed, and all studies included were randomized. Four studies reported the responses to enzyme replacement therapy of previously untreated individuals with type 1 Gaucher Disease. Two studies investigated maintenance enzyme replacement therapy in people with stable type 1 Gaucher Disease previously treated for at least two years. One study compared substrate reduction therapy, enzyme replacement therapy and a combination thereof as maintenance therapy in people with type 1 Gaucher Disease previously treated with enzyme replacement therapy. One study examined substrate reduction therapy in people with chronic neuronopathic (type 3) Gaucher Disease who continued to receive enzyme replacement therapy. Treatment-naive participants had similar increases in haemoglobin when comparing those receiving imiglucerase or alglucerase at 60 units/kg, imiglucerase or velaglucerase alfa at 60 U/kg, taliglucerase alfa at 30 units/kg or 60 units/kg, and velaglucerase alfa at 45 units/g or 60 units/kg. For platelet count response in participants with intact spleens, a benefit for imiglucerase over velaglucerase alfa at 60 units/kg was observed, mean difference -79.87 (95% confidence interval -137.57 to -22.17). There were no other significant differences in platelet count response when comparing different doses of velaglucerase alfa and of taliglucerase alfa, and when comparing imiglucerase to alglucerase. Spleen and liver volume reductions were not significantly different in any enzyme replacement therapy product or dose comparison study. Although a dose effect on serum biomarkers was not seen after nine months, a significantly greater reduction with higher dose was reported after 12 months in the velaglucerase study, mean difference 16.70 (95% confidence intervaI 1.51 to 31.89). In the two enzyme replacement therapy maintenance studies comparing infusions every two weeks and every four weeks, there were no significant differences in haemoglobin concentration, platelet count, and spleen and liver volumes over a 6 to 12 month period when participants were treated with the same cumulative dose. A total of 25 serious adverse events were reported, nearly all deemed unrelated to treatment. There are, as yet, no randomized trials of substrate reduction therapy in treatment-naive patients that can be evaluated. Miglustat monotherapy appeared as effective as continued enzyme replacement therapy for maintenance of hematological, organ and biomarker responses in people with type 1 Gaucher Disease previously treated with imiglucerase for at least two years. In those with neuronopathic Gaucher Disease, no significant improvements in haemoglobin concentration, platelet count or organ volumes occurred when enzyme replacement therapy was augmented with miglustat. One randomized controlled study assessing substrate reduction therapy was published immediately prior to producing the final version of this review, and this, along with a further ongoing study (expected to be published in the near future), will be assessed for eligibility in a future update of the review. Authors' conclusions The results reflect the limitations of analysing evidence restricted to prospective randomized controlled trials, especially when dealing with chronic rare Diseases. This analysis suggests that, during the first year of treatment, different recombinant glucocerebrosidases are bio-similar and non-inferior in safety and efficacy for surrogate biological response parameters. Enzyme replacement therapy given at 30 to 45 units/kg body weight every two to four weeks was generally as effective as the 60 unit/kg dose for the assessed clinical outcomes. The analysis emphasise the need to determine whether it is realistic to carry out multi-decade prospective clinical trials for rare Diseases such as type 1 Gaucher Disease. With large treatment effects on the classical manifestations of the disorder, therapeutic investigations in Gaucher Disease mandate innovative trial designs and methodology to secure decisive data concerning long-term efficacy and safety – with the realization that knowledge about Disease-modifying actions that are sustained are of crucial importance to people with this chronic condition.
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Gaucher Disease: A Comprehensive Review
Critical Reviews in Oncogenesis, 2013Co-Authors: Barry E. Rosenbloom, Neal J. WeinrebAbstract:Gaucher Disease (GD) is an inherited error of metabolism due to a deficiency of glucocerebrosidase. This leads to excessive storage of glucocerebroside in the liver, spleen, bone, and bone marrow. Patients develop anemia, thrombocytopenia, hepatosplenomegaly, bone infarcts, aseptic necrosis of bone, and osteoporosis. There are three types of GD; types 2 and 3 have neurological involvement. With the advent of enzyme replacement therapy and substrate reduction therapy, the natural history of the Disease has been has significantly changed, with a marked decrease in morbidity, especially for type 1 patients. This article reviews a broad spectrum of information regarding Gaucher Disease, from the history of the Disease to newer therapies still in the investigational stage.
Ellen Sidransky - One of the best experts on this subject based on the ideXlab platform.
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ophthalmological findings in Gaucher Disease
Molecular Genetics and Metabolism, 2019Co-Authors: Areian Eghbali, Shahzeb Hassan, Gurpreet Seehra, Edmond J Fitzgibbon, Ellen SidranskyAbstract:Abstract Gaucher Disease is an autosomal recessive lysosomal storage disorder caused by mutations in the gene GBA1, which encodes the lysosomal protein glucocerebrosidase. Patients with Gaucher Disease generally have a variety of clinical manifestations ranging from visceral to neurological involvement and some develop ocular involvement. The most commonly affected organs include the spleen, liver, and bone. Moreover, patients often have hepatosplenomegaly, thrombocytopenia, anemia, and bone involvement related to deficient glucocerebrosidase and the subsequent accumulation of glucosylceramide and glucosylsphingosine in cells. A subset of patients develops neurological manifestations, including seizures, myoclonic epilepsy, and progressive neurodegeneration. Eye involvement tends to be less common and presents with diverse clinical findings. These rare and variable ocular manifestations, involving the vitreous, retina, cornea, uvea, conjunctiva and eye movements, can pose a diagnostic challenge for clinicians, especially those not familiar with the disorder. In this review, we explore the different ophthalmologic findings reported in patients with Gaucher Disease, aiming to facilitate diagnosis and expedite treatment for patients presenting with ocular manifestations of this rare disorder.
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exploring genetic modifiers of Gaucher Disease the next horizon
Human Mutation, 2018Co-Authors: Brad Davidson, Shahzeb Hassan, Nahid Tayebi, Eric Joshua Garcia, Ellen SidranskyAbstract:Gaucher Disease is an autosomal recessive lysosomal storage disorder resulting from mutations in the gene GBA1 that lead to a deficiency in the enzyme glucocerebrosidase. Accumulation of the enzyme's substrates, glucosylceramide and glucosylsphingosine, results in symptoms ranging from skeletal and visceral involvement to neurological manifestations. Nonetheless, there is significant variability in clinical presentations amongst patients, with limited correlation between genotype and phenotype. Contributing to this clinical variation are genetic modifiers that influence the phenotypic outcome of the disorder. In this review, we explore the role of genetic modifiers in Mendelian disorders and describe methods to facilitate their discovery. In addition, we provide examples of candidate modifiers of Gaucher Disease, explore their relevance in the development of potential therapeutics, and discuss the impact of GBA1 and modifying mutations on other more common Diseases like Parkinson Disease. Identifying these important modulators of Gaucher phenotype may ultimately unravel the complex relationship between genotype and phenotype and lead to improved counseling and treatments.
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Gaucher Disease progress and ongoing challenges
Molecular Genetics and Metabolism, 2017Co-Authors: Pramod K. Mistry, Neal J. Weinreb, Raphael Schiffmann, Grisel Lopez, Norman W Barton, Ellen SidranskyAbstract:Over the past decades, tremendous progress has been made in the field of Gaucher Disease, the inherited deficiency of the lysosomal enzyme glucocerebrosidase. Many of the colossal achievements took place during the course of the sixty-year tenure of Dr. Roscoe Brady at the National Institutes of Health. These include the recognition of the enzymatic defect involved, the isolation and characterization of the protein, the localization and characterization of the gene and its nearby pseudogene, as well as the identification of the first mutant alleles in patients. The first treatment for Gaucher Disease, enzyme replacement therapy, was conceived of, developed and tested at the Clinical Center of the National Institutes of Health. Advances including recombinant production of the enzyme, the development of mouse models, pioneering gene therapy experiments, high throughput screens of small molecules and the generation of induced pluripotent stem cell models have all helped to catapult research in Gaucher Disease into the twenty-first century. The appreciation that mutations in the glucocerebrosidase gene are an important risk factor for parkinsonism further expands the impact of this work. However, major challenges still remain, some of which are described here, that will provide opportunities, excitement and discovery for the next generations of Gaucher investigators.
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the clinical management of type 2 Gaucher Disease
Molecular Genetics and Metabolism, 2015Co-Authors: Karin Weiss, Ashley N Gonzalez, Grisel Lopez, Leah Pedoeim, Catherine Groden, Ellen SidranskyAbstract:Gaucher Disease, the inherited deficiency of the enzyme glucocerebrosidase, is the most common of the lysosomal storage disorders. Type 2 Gaucher Disease, the most severe and progressive form, manifests either prenatally or in the first months of life, followed by death within the first years of life. The rarity of the many lysosomal storage disorders makes their diagnosis a challenge, especially in the newborn period when the focus is often on more prevalent illnesses. Thus, a heightened awareness of the presentation of these rare Diseases is necessary to ensure their timely consideration. This review, designed to serve as a guide to physicians treating newborns and infants with Gaucher Disease, discusses the presenting manifestations of Type 2 Gaucher Disease, the diagnostic work-up, associated genotypes and suggestions for management. We also address the ethical concerns that may arise with this progressive and lethal disorder, since currently available treatments may prolong life, but do not impact the neurological manifestations of the Disease.
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Gaucher Disease insights from a rare mendelian disorder
Discovery Medicine, 2012Co-Authors: Ellen SidranskyAbstract:It is becoming quite evident that studies of Mendelian disorders can provide important insights into common neurologic disorders. These rare inherited disorders often offer a unique window into seemingly unrelated Diseases. The number of studies focusing on genetic contributions to neurologic disorders is growing exponentially. When undertaking the challenges associated with identifying the genes underlying complex neurological disorders, it is valuable to consider lessons gleaned from decades of studies of rare Mendelian disorders. This review will focus on lessons learned and challenges encountered in the study of one such monogenic disorder, Gaucher Disease, focusing both on purely clinical observations, as well as the impact of such insights on understanding more common complex Diseases. Studies of patients with Gaucher Disease have led to unanticipated research directions impacting several distinct medical disciplines. Some notable examples include the link between mutations in the glucocerebrosidase gene and the development of Parkinson Disease and related Lewy body disorders, elucidation of the role of glucocerebrosidase in skin barrier function and neonatal viability, and the connection between lysosomal transport and myoclonic epilepsy.
Pramod K. Mistry - One of the best experts on this subject based on the ideXlab platform.
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Gaucher Disease in bone from pathophysiology to practice
Journal of Bone and Mineral Research, 2019Co-Authors: Derralynn Hughes, Ozlem Gokeralpan, Nadia Belmatoug, Pramod K. Mistry, Timothy M Cox, P Mikosch, Francesca Carubbi, Andreas Kindmark, L W Poll, Neal J. WeinrebAbstract:Gaucher Disease (GD) is a rare, genetic lysosomal disorder leading to lipid accumulation and dysfunction in multiple organs. Involvement of the skeleton is one of the most prevalent aspects of GD a ...
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Reversal of life-threatening hepatopulmonary syndrome in Gaucher Disease by imiglucerase enzyme replacement therapy.
Molecular Genetics and Metabolism Reports, 2019Co-Authors: Amal El Beshlawy, Vagishwari Murugesan, Pramod K. Mistry, Khaled EidAbstract:Abstract Advanced liver Disease complicated by hepatopulmonary syndrome is a recognized complication of Gaucher Disease. Macrophage-targeted, recombinant enzyme replacement therapy is effective in reversing clinical manifestations attributed to the accumulation of glycolipid-laden macrophages but it is not known whether advanced fibrotic features of the Disease can be ameliorated. We describe a splenectomized patient with Gaucher Disease who developed massive hepatomegaly, cirrhosis of the liver and life-threatening hepatopulmonary syndrome. Treatment with Imiglucerase enzyme replacement therapy resulted in dramatic reversal of hepatopulmonary syndrome and liver Disease. Our report suggests that Gaucher Disease pathology involving advanced fibrosis and life-threatening complications can be reversed by imiglucerase enzyme therapy. Synopsis Effect of imiglucerase enzyme replacement therapy on Hepatopulmonary Syndrome in Gaucher Disease.
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Gaucher Disease progress and ongoing challenges
Molecular Genetics and Metabolism, 2017Co-Authors: Pramod K. Mistry, Neal J. Weinreb, Raphael Schiffmann, Grisel Lopez, Norman W Barton, Ellen SidranskyAbstract:Over the past decades, tremendous progress has been made in the field of Gaucher Disease, the inherited deficiency of the lysosomal enzyme glucocerebrosidase. Many of the colossal achievements took place during the course of the sixty-year tenure of Dr. Roscoe Brady at the National Institutes of Health. These include the recognition of the enzymatic defect involved, the isolation and characterization of the protein, the localization and characterization of the gene and its nearby pseudogene, as well as the identification of the first mutant alleles in patients. The first treatment for Gaucher Disease, enzyme replacement therapy, was conceived of, developed and tested at the Clinical Center of the National Institutes of Health. Advances including recombinant production of the enzyme, the development of mouse models, pioneering gene therapy experiments, high throughput screens of small molecules and the generation of induced pluripotent stem cell models have all helped to catapult research in Gaucher Disease into the twenty-first century. The appreciation that mutations in the glucocerebrosidase gene are an important risk factor for parkinsonism further expands the impact of this work. However, major challenges still remain, some of which are described here, that will provide opportunities, excitement and discovery for the next generations of Gaucher investigators.
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Validating glycoprotein non-metastatic melanoma B (gpNMB, osteoactivin), a new biomarker of Gaucher Disease
Blood Cells Molecules and Diseases, 2016Co-Authors: Vagishwari Murugesan, Jun Liu, Ruhua Yang, Haiquin Lin, Andrew Lischuk, Gregory M. Pastores, Xiaokui Zhang, Wei-lien Chuang, Pramod K. MistryAbstract:In the spleens of Gaucher Disease mice and patients, there is a striking elevation of expression of glycoprotein non-Metastatic Melanoma B (gpNMB). We conducted a study in a large cohort of patients with Gaucher Disease to assess the utility of serum levels of soluble fragment of gpNMB as a biomarker of Disease activity. There was >15-fold elevation of gpNMB in sera of untreated patients with Gaucher Disease. gpNMB levels correlated with overall Disease severity as well as the severity of individual organ compartments: liver, spleen, bone and hematological Disease. Imiglucerase enzyme replacement therapy resulted in significant reduction of gpNMB. Serum levels of gpNMB were highly correlated with accumulation of bioactive lipid substrate of Gaucher Disease, glucosylsphingosine as well as established biomarkers, chitotriosidase and chemokine, CCL18. Our results suggest utility of gpNMB as a biomarker of Gaucher Disease to monitor individual patients and cohorts of patients for Disease progression or response to therapy. Investigation of gpNMB in Gaucher Disease pathophysiology is likely to illuminate our understanding Disease mechanisms.
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recommendations for the use of eliglustat in the treatment of adults with Gaucher Disease type 1 in the united states
Molecular Genetics and Metabolism, 2016Co-Authors: Manisha Balwani, Ozlem Gokeralpan, Pramod K. Mistry, Priya S. Kishnani, Paige Kaplan, Joel Charrow, Thomas A Burrow, Jeremy N Ruskin, Neal J. WeinrebAbstract:In Gaucher Disease, deficient activity of acid β-glucosidase results in accumulation of its substrates, glucosylceramide and glucosylsphingosine, within the lysosomes of cells primarily in the spleen, liver, bone marrow, and occasionally the lung. The multisystem Disease is predominantly characterized by hepatosplenomegaly, anemia, thrombocytopenia, and skeletal Disease. Enzyme replacement therapy with recombinant human acid β-glucosidase has been the first-line therapy for Gaucher Disease type 1 for more than two decades. Eliglustat, a novel oral substrate reduction therapy, was recently approved in the United States and the European Union as a first-line treatment for adults with Gaucher Disease type 1. Eliglustat inhibits glucosylceramide synthase, thereby decreasing production of the substrate glucosylceramide and reducing its accumulation. Although existing recommendations for the care of patients with Gaucher Disease remain in effect, unique characteristics of eliglustat require additional investigation and monitoring. A panel of physicians with expertise in Gaucher Disease and experience with eliglustat in the clinical trials provide guidance regarding the use of eliglustat, including considerations before starting therapy and monitoring of patients on eliglustat therapy.
Gregory A. Grabowski - One of the best experts on this subject based on the ideXlab platform.
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Gaucher Disease types 1 and 3 phenotypic characterization of large populations from the icgg Gaucher registry
American Journal of Hematology, 2015Co-Authors: Gregory A. Grabowski, Ari Zimran, Hiroyuki IdaAbstract:Study of the natural history of Gaucher Disease has revealed marked phenotypic variation. Correlations to genotypes could provide insight into individual susceptibility to varying Disease severity, which may impact whole-life medical care, reproductive decisions, and therapeutic choices for affected families. Importantly, pre-symptomatic or prospective interventions or the use of therapies with significant risk require accurate risk-benefit analyses based on the prognosis for individual patients. The body of international data held within the International Collaborative Gaucher Group (ICGG) Gaucher Registry provides an unprecedented opportunity to characterize the phenotypes of Gaucher Disease types 1 and 3 and to appreciate demographic and ethnic factors that may influence phenotypes. The diversity of GBA gene mutations from patients with Gaucher Disease represented in the ICGG Gaucher Registry database and in the literature provides the basis for initial genotype/phenotype correlations, the outcomes of which are summarized here.Am. J. Hematol. 90:S12–S18, 2015. © 2015 Wiley Periodicals, Inc.
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Gaucher Disease and other storage disorders
Hematology, 2012Co-Authors: Gregory A. GrabowskiAbstract:In 1882, Philippe Gaucher described a 32-year-old woman with massive splenomegaly and unusually large cells in the spleen, which he called a "primary epithelioma of the spleen." The systemic nature and inheritance of the Disease and its variants involving the viscera and CNS were described over the next century. The delineation of the causal enzymatic defects, genetics, molecular pathology, and genomics have provided pathogenic insights into the phenotypic spectrum and the bases for development of specific therapies for what is now known as Gaucher Disease. As a prototype, the clinically and economically successful intracellular enzyme therapy provided the impetus for the expansion of similar research and therapeutic developments for other lysosomal storage Diseases (LSDs) and orphan Diseases, including Fabry, Pompe, and Niemann-Pick Diseases, as well as several mucopolysaccharidoses. Continuing studies of such LSDs, which occur as a group in more than 7000 live births, have revealed the complex molecular interdigitation with the autophagy and apoptotic pathways and proteostasis and the impact of disruptions of the lysosomal/autophagy and proteostasis systems on more common Diseases has been recognized. Examples include age-related neurodegenerative Diseases (eg, Parkinson Disease and Gaucher Disease), idiopathic hypertrophic myocardiopathies, stroke and renal failure (eg, Fabry Disease), and Nonalcoholic Fatty Liver Disease/Nonalcoholic SteatoHepatitis (NAFLD/NASH) and atherosclerosis (eg, lysosomal acid lipase deficiencies). Although perceived as rare, the availability of treatment and the impact of the LSDs on more common Diseases require their integration into routine clinical practice.
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a specific and potent inhibitor of glucosylceramide synthase for substrate inhibition therapy of Gaucher Disease
Molecular Genetics and Metabolism, 2007Co-Authors: Kerry Anne Mceachern, Johannes M F G Aerts, Wei-lien Chuang, Gregory A. Grabowski, John J Fung, Svetlana Komarnitsky, Craig Siegel, Elizabeth Hutto, James A Shayman, Seng H ChengAbstract:An approach to treating Gaucher Disease is substrate inhibition therapy which seeks to abate the aberrant lysosomal accumulation of glucosylceramide. We have identified a novel inhibitor of glucosylceramide synthase (Genz-112638) and assessed its activity in a murine model of Gaucher Disease (D409V/null). Biochemical characterization of Genz-112638 showed good potency (IC(50) approximately 24nM) and specificity against the target enzyme. Mice that received drug prior to significant accumulation of substrate (10 weeks of age) showed reduced levels of glucosylceramide and number of Gaucher cells in the spleen, lung and liver when compared to age-matched control animals. Treatment of older mice that already displayed significant amounts of tissue glucosylceramide (7 months old) resulted in arrest of further accumulation of the substrate and appearance of additional Gaucher cells in affected organs. These data indicate that substrate inhibition therapy with Genz-112638 represents a viable alternate approach to enzyme therapy to treat the visceral pathology in Gaucher Disease.
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therapeutic goals in the treatment of Gaucher Disease
Seminars in Hematology, 2004Co-Authors: Gregory M. Pastores, Neal J. Weinreb, Pramod K. Mistry, Gregory A. Grabowski, Hans Aerts, Generoso Andria, Timothy M Cox, Manuel Giralt, Anna TylkiszymanskaAbstract:Gaucher Disease, the most common lysosomal storage disorder, is a heterogeneous multisystem condition. Patients with non-neuronopathic (type 1) Gaucher Disease may suffer from hepatomegaly, splenomegaly, thrombocytopenia, bleeding tendencies, anemia, hypermetabolism, skeletal pathology, growth retardation, pulmonary Disease, and decreased quality of life. Enzyme replacement therapy (ERT) with mannose-terminated glucocerebrosidase reverses or ameliorates many of the manifestations of type 1 Gaucher Disease. However, the variable Disease pattern and severity, and the uncertain manner of progression, render the decision to initiate ERT difficult. Thus, implementation of treatment and evaluation of the therapeutic response must be tailored to the individual patient. To obtain an evidence-based consensus on contemporary therapeutic goals, an international panel of physicians with extensive clinical experience in Gaucher Disease met to review the extant literature on its treatment. The panel adopted an integrated system-based approach to arrive at a comprehensive guide to individualized management. Here we establish goals of treatment in Gaucher Disease and propose a comprehensive schedule of monitoring of all relevant aspects to confirm the achievement, maintenance, and continuity of the therapeutic response.
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enzyme therapy for Gaucher Disease the first 5 years
Blood Reviews, 1998Co-Authors: Gregory A. Grabowski, N Leslie, R WenstrupAbstract:Abstract Gaucher Disease was first described by Philippe Gaucher in his 1882 medical thesis. Gaucher's original concept was of an unusual epithelioma of the spleen. By the early 1900s, Mandelbaum recognized the systemic nature of the Disease. Several children with Gaucher Disease were described at the turn of the century, but Rusca3 described a rapidly progressive fatal neurodegenerative type of Disease, i.e. type 2, in the 1920s. The ‘juvenile’ form (type 3) of the Disease was described in Sweden in the 1950s. In 1965, the deficient enzyme, acid β-glucosidase, was discovered and the lysosomal nature of the Disease was elucidated. Currently, three variants of Gaucher Disease have been defined clinically and are distinguished by the presence and severity of neuronopathic involvement (Table 1). Each of these clinical types has substantial phenotypic variation, but types 1 and 3 have significantly heterogeneous rates of Disease progression and degrees of visceral organs involvement. The neuronopathic involvement in type 3 also has substantial variation in the age of onset and Disease progression even within relatively isolated communities. An extensive review of the clinical and pathologic involvement by Gaucher Disease is available.
Nadia Belmatoug - One of the best experts on this subject based on the ideXlab platform.
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Gaucher Disease in bone from pathophysiology to practice
Journal of Bone and Mineral Research, 2019Co-Authors: Derralynn Hughes, Ozlem Gokeralpan, Nadia Belmatoug, Pramod K. Mistry, Timothy M Cox, P Mikosch, Francesca Carubbi, Andreas Kindmark, L W Poll, Neal J. WeinrebAbstract:Gaucher Disease (GD) is a rare, genetic lysosomal disorder leading to lipid accumulation and dysfunction in multiple organs. Involvement of the skeleton is one of the most prevalent aspects of GD a ...
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intra monocyte pharmacokinetics of imiglucerase supports a possible personalized management of Gaucher Disease type 1
Clinical Pharmacokinectics, 2019Co-Authors: Juliette Berger, Nadia Belmatoug, Christian Rose, Florence Dalbies, A Masseau, Marie Vigan, Bruno Pereira, Thu Thuy Nguyen, Roseline Froissart, Christine SerratriceAbstract:Intravenous imiglucerase enzyme replacement therapy for Gaucher Disease type 1 administered every 2 weeks is at variance with the imiglucerase plasma half-life of a few minutes. We hypothesized that studying the pharmacokinetics of imiglucerase in blood Gaucher Disease type 1 monocytes would be more relevant for understanding enzyme replacement therapy responses. Glucocerebrosidase intra-monocyte activity was studied by flow cytometry. The pharmacokinetics of imiglucerase was analyzed using a population-pharmacokinetic model from a cohort of 31 patients with Gaucher Disease type 1 who either started or were receiving long-term treatment with imiglucerase. A pharmacokinetic analysis of imiglucerase showed a two-compartment model with a high peak followed by a two-phase exponential decay (fast phase half-life: 0.36 days; slow phase half-life: 9.7 days) leading to a median 1.4-fold increase in glucocerebrosidase intra-monocyte activity from the pre-treatment activity (p = 0.04). In patients receiving long-term treatment, for whom the imiglucerase dose per infusion was chosen on the basis of Disease aggressiveness/response, imiglucerase clearance correlated with the administered dose. However, the residual glucocerebrosidase intra-monocyte activity value was dose independent, suggesting that the maintenance of imiglucerase residual activity is patient specific. Endogenous pre-treatment glucocerebrosidase intra-monocyte activity was the most informative single parameter for distinguishing patients without (n = 10) and with a clinical indication (n = 17) for starting enzyme replacement therapy (area under the receiver operating characteristic curve: 0.912; 95% confidence interval 0.8–1; p < 0.001), as confirmed also by a factorial analysis of mixed data. This study provides novel pharmacokinetic data that support current imiglucerase administration regimens and suggests the existence of a glucocerebrosidase activity threshold related to Gaucher Disease type 1 aggressiveness. These findings can potentially improve Gaucher Disease type 1 management algorithms and clinical decision making.
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splenic artery aneurysms a rare complication of type 1 Gaucher Disease report of five cases
Journal of Clinical Medicine, 2019Co-Authors: Christine Serratrice, Vanessa Leguyseguin, E M Morris, Karima Yousfi, Olivier Monnet, Annie Sibert, Wassim Allaham, Nadia BelmatougAbstract:Type 1 Gaucher Disease is a rare genetic lysosomal disorder due to acid betaglucosidase deficiency. The main features are thrombocytopenia, anemia, hepatosplenomegaly and complex skeletal Disease. Complications include pulmonary hypertension, cirrhosis and splenic infarction; comorbidities, such as autoimmune phenomena, B-cell malignancies and Parkinson Disease also occur. Visceral aneurysms have been only rarely noted in Gaucher Disease. We report the retrospective data from patients with Gaucher Disease type 1 and splenic arterial aneurysm. We describe the different outcomes of a giant splenic arterial aneurysm in five patients with type 1 Gaucher Disease and discuss the main possible pathophysiological explanations. Aneurysms of the splenic artery are rare in Gaucher Disease but are probably greatly under-reported.
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Unexpected macrophage-independent dyserythropoiesis in Gaucher Disease
Haematologica, 2016Co-Authors: Niloofar Reihani, Jean-benoît Arlet, Michael Dussiot, Olivier Hermine, Nadia Belmatoug, Caroline Le Van Kim, Thierry Billette De Villemeur, Christian Rose, Yves Colin Aronovicz, Mélanie FrancoAbstract:Gaucher Disease is a rare inherited Disease caused by a deficiency in glucocerebrosidase leading to lipid accumulation in cells of mononuclear-macrophage lineage known as Gaucher cells. Visceral enlargement, bone involvement, mild anemia and thrombocytopenia are the major manifestations of Gaucher Disease. We have previously demonstrated that the red blood cells from patients exhibit abnormal properties, which indicates a new role in Gaucher Disease pathophysiology. To investigate whether erythroid progenitors are affected, we examined the in vitro erythropoiesis from the peripheral CD34+ cells of patients and controls. CD34− cells were differentiated into macrophages and co-cultivated with erythroblasts. We showed an accelerated differentiation of erythroid progenitors without maturation arrest from patients compared to controls. This abnormal differentiation persisted in the patients when the same experiments were performed without macrophages, which strongly suggested that dyserythropoiesis in Gaucher Disease is secondary to an inherent defect in the erythroid progenitors. The accelerated differentiation was associated with reduced cell proliferation. As a result, less mature erythroid cells were generated in vitro in the Gaucher Disease cultures compared to the control. We then compared the biological characteristics of untreated patients according to their anemic status. Compared to the non-anemic group, the anemic patients exhibit higher plasma levels of growth differentiation factor-15, a marker of ineffective erythropoiesis, but they had no indicators of hemolysis and similar reticulocyte counts. Taken together, these results demonstrated an unsuspected dyserythropoiesis that was independent of the macrophages and could participate, at least in part, to the basis of anemia in Gaucher Disease.
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Management and monitoring recommendations for the use of eliglustat in adults with type 1 Gaucher Disease in Europe.
European Journal of Internal Medicine, 2016Co-Authors: Nadia Belmatoug, Cristina Fraga, Elena Lukina, Martin Merkel, Derralynn Hughes, Pierre Maison-blanche, Claus Niederau, Pilar Giraldo, Maja Di Rocco, Ursula PlӧckingerAbstract:Abstract Purpose In Gaucher Disease, diminished activity of the lysosomal enzyme, acid β-glucosidase, leads to accumulation of glucosylceramides and related substrates, primarily in the spleen, liver, and bone marrow. Eliglustat is an oral substrate reduction therapy approved in the European Union and the United States as a first-line treatment for adults with type 1 Gaucher Disease who have compatible CYP2D6 metabolism phenotypes. A European Advisory Council of experts in Gaucher Disease describes the characteristics of eliglustat that are distinct from enzyme augmentation therapy (the standard of care) and miglustat (the other approved substrate reduction therapy) and recommends investigations and monitoring for patients on eliglustat therapy within the context of current recommendations for Gaucher Disease management. Results Eliglustat is a selective, potent inhibitor of glucosylceramide synthase, the enzyme responsible for biosynthesis of glucosylceramides which accumulate in Gaucher Disease. Extensive metabolism of eliglustat by CYP2D6, and, to a lesser extent, CYP3A of the cytochrome P450 pathway, necessitates careful consideration of the patient's CYP2D6 metaboliser status and use of concomitant medications which share metabolism by these pathways. Guidance on specific assessments and monitoring required for eliglustat therapy, including an algorithm to determine eligibility for eliglustat, are provided. Conclusions As a first-line therapy for type 1 Gaucher Disease, eliglustat offers eligible patients a daily oral therapy alternative to biweekly infusions of enzyme therapy. Physicians will need to carefully assess individual Gaucher patients to determine their appropriateness for eliglustat therapy. The therapeutic response to eliglustat and use of concomitant medications will require long-term monitoring.