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"Substrate reduction therapy "

Luba Nalysnyk, Rebecca Sugarman, Clifford Cele, Jennifer Uyei, Alexandra Ward
BACKGROUND: Gaucher disease type 1 (GD1) is a rare, genetic, lysosomal storage disease with no cure. Current treatment options include intravenous (IV) enzyme replacement therapy ([ERT]; imiglucerase, velaglucerase alfa, or taliglucerase alfa) or oral substrate reduction therapy ([SRT]; eliglustat or miglustat). The cost to U.S. payers of an IV-administered drug can vary depending on the site of care (i.e., home, outpatient clinic, or hospital setting). Treatment with oral eliglustat may present an opportunity for cost savings...
October 2018: Journal of Managed Care & Specialty Pharmacy
Sofya Pchelina, Galina Baydakova, Mikhael Nikolaev, Konstantin Senkevich, Anton Emelyanov, Alena Kopytova, Irina Miliukhina, Andrey Yakimovskii, Alla Timofeeva, Olga Berkovich, Ekatrina Fedotova, Sergey Illarioshkin, Ekaterina Zakharova
INTRODUCTION: Glucocerebrosidase 1 mutations, the most common genetic contributor to Parkinson's disease (PD), have been associated with decreased glucocerebrosidase enzymatic activity in PD patients with glucocerebrosidase 1 mutations (glucocerebrosidase 1-PD). However, it is unknown whether this decrease in enzymatic activity leads to lysosphingolipid accumulations. METHODS: The levels of hexosylsphingosines, globotriaosylsphingosine, sphingomyelin, and sphingomyelin-509 were measured in dried blood spots from glucocerebrosidase 1-PD patients (n = 23), sporadic PD patients (n = 105), Gaucher disease patients (n = 32), and controls (n = 88) by liquid chromatography-tandem mass spectrometry...
August 2018: Movement Disorders: Official Journal of the Movement Disorder Society
Roberto Giugliani, Filippo Vairo, Francyne Kubaski, Fabiano Poswar, Mariluce Riegel, Guilherme Baldo, Jonas Alex Saute
Lysosomal disorders have been an area of interest since intravenous enzyme replacement therapy was successfully introduced for the treatment of Gaucher's disease in the early 1990s. This treatment approach has also been developed for several other lysosomal disorders, including Fabry's disease, Pompe's disease, lysosomal acid lipase deficiency, and five types of mucopolysaccharidosis. Despite the benefits of enzyme replacement therapy, it has limitations-most importantly, its ineffectiveness in treating the neurological components of lysosomal disorders, as only a small proportion of recombinant enzymes can cross the blood-brain barrier...
January 2018: Lancet Child & Adolescent Health
Molly Stapleton, Hiroo Hoshina, Kazuki Sawamoto, Francyne Kubaski, Robert W Mason, William G Mackenzie, Mary Theroux, Hironori Kobayashi, Seiji Yamaguchi, Yasuyuki Suzuki, Toshiyuki Fukao, Orii Tadao, Hiroyuki Ida, Shunji Tomatsu
Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders that impair degradation of glycosaminoglycans (GAG). The specific GAGs that accumulate depend on the type of MPS, leading to unique characteristic clinical features. Development of guidelines for treatment of MPS has traditionally been multifaceted and largely based on palliative care. In the last three decades, hematopoietic stem cell transplantation and enzyme replacement therapy have been developed based on experimental and clinical studies...
July 7, 2018: Molecular Genetics and Metabolism
Sam E Gary, Emory Ryan, Alta M Steward, Ellen Sidransky
Gaucher disease, the autosomal recessive deficiency of the lysosomal enzyme glucocerebrosidase, is associated with wide phenotypic diversity including non-neuronopathic, acute neuronopathic, and chronic neuronopathic forms. Overlap between types can render definitive diagnoses difficult. However, differentiating between the different phenotypes is essential due to the vast differences in clinical outcomes and response to therapy. Genotypic information is helpful, but cannot always be used to make clinical predictions...
March 2018: Expert Review of Endocrinology & Metabolism
Miguel-Ángel Torralba-Cabeza, Susana Olivera-González, José-Luis Sierra-Monzón
Managing the multisystemic symptoms of type I Gaucher Disease (GD) requires a multidisciplinary team approach that includes disease-specific treatments, as well as supportive care. This involves a range of medical specialists, general practitioners, supportive care providers, and patients. Phenotype classification and the setting of treatment goals are important for optimizing the management of type I GD, and for providing personalized care. The ability to classify disease severity using validated measurement tools allows the standardization of patient monitoring, and the measurement of disease progression and treatment response...
July 26, 2018: Diseases (Basel)
Huan Yang, Musa Male, Yang Li, Ning Wang, Chenming Zhao, Shan Jin, Juncheng Hu, Zhiqiang Chen, Zhangqun Ye, Hua Xu
BACKGROUND: Substrate reduction therapy with analogs reduces the accumulation of substrates by inhibiting the metabolic pathways involved in their biosynthesis, providing new treatment options for patients with primary hyperoxalurias (PHs) that often progress to end-stage renal disease (ESRD). This research aims to evaluate the inhibition efficacy of Hydroxy-L-proline (HYP) analogs against calcium oxalate (CaOx) crystal formation in the Drosophila Melanogaster (D. Melanogaster) by comparing them with Pyridoxine (Vitamin B6)...
July 6, 2018: BMC Nephrology
Valeria De Pasquale, Patrizia Sarogni, Valeria Pistorio, Giuliana Cerulo, Simona Paladino, Luigi Michele Pavone
Mucopolysaccharidoses (MPSs) are inherited metabolic diseases caused by the deficiency of lysosomal enzymes needed to catabolize glycosaminoglycans (GAGs). Four therapeutic options are currently considered: enzyme replacement therapy, substrate reduction therapy, gene therapy, and hematopoietic stem cell transplantation. However, while some of them exhibit limited clinical efficacy and require high costs, others are still in development. Therefore, alternative treatments for MPSs need to be explored. Here we describe an innovative therapeutic approach based on the use of a recombinant protein that is able to bind the excess of extracellular accumulated heparan sulfate (HS)...
September 21, 2018: Molecular Therapy. Methods & Clinical Development
Chengjung Lai, Natalie Pursell, Jessica Gierut, Utsav Saxena, Wei Zhou, Michael Dills, Rohan Diwanji, Chaitali Dutta, Martin Koser, Naim Nazef, Rachel Storr, Boyoung Kim, Cristina Martin-Higueras, Eduardo Salido, Weimin Wang, Marc Abrams, Henryk Dudek, Bob D Brown
Primary hyperoxalurias (PHs) are autosomal recessive disorders caused by the overproduction of oxalate leading to calcium oxalate precipitation in the kidney and eventually to end-stage renal disease. One promising strategy to treat PHs is to reduce the hepatic production of oxalate through substrate reduction therapy by inhibiting liver-specific glycolate oxidase (GO), which controls the conversion of glycolate to glyoxylate, the proposed main precursor to oxalate. Alternatively, diminishing the amount of hepatic lactate dehydrogenase (LDH) expression, the proposed key enzyme responsible for converting glyoxylate to oxalate, should directly prevent the accumulation of oxalate in PH patients...
August 1, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Shoshana Revel-Vilk, Jeff Szer, Atul Mehta, Ari Zimran
Treatment of Gaucher Disease (GD) is now beset with the abundance of therapeutic options for an individual patient, making the choice of therapy complex for both expert and non-expert clinicians. The pathogenesis of all disease manifestations is a gene mutation-driven deficiency of glucocerebrosidase, but the clinical expression and response of each of the clinical manifestations to different therapies can be difficult to predict. Enzyme replacement therapy has been available since 1991 and is well-established, with known efficacy and minimal toxicity...
August 2018: British Journal of Haematology
Erika R Vucko
: Lysosomal storage disorders (LSDs) are a group of inherited metabolic conditions, the overall incidence of which is estimated to range from one in 5,000 to one in 7,000 live births. Gaucher disease, the most common LSD, is of autosomal recessive inheritance. It results from a deficiency of acid β-glucocerebrosidase and can affect the spleen, liver, bone, bone marrow, and central nervous system. Gaucher disease is clinically classified into one of three phenotypes, depending on the absence or presence of neurodegenerative disease and the rate of disease progression...
June 2018: American Journal of Nursing
Maria Begona Cachon-Gonzalez, Eva Zaccariotto, Timothy Martin Cox
Tay-Sachs disease, caused by impaired β-N-acetylhexosaminidase activity, was the first GM2 gangliosidosis to be studied and one of the most severe and earliest lysosomal diseases to be described. The condition, associated with the pathological build-up of GM2 ganglioside, has acquired almost iconic status and serves as a paradigm in the study of lysosomal storage diseases. Inherited as a classical autosomal recessive disorder, this global disease of the nervous system induces developmental arrest with regression of attained milestones; neurodegeneration progresses rapidly to cause premature death in young children...
2018: Current Gene Therapy
Roberta Balestrino, Anthony H V Schapira
Parkinson disease (PD) is a complex neurodegenerative disease characterised by multiple motor and non-motor symptoms. In the last 20 years, more than 20 genes have been identified as causes of parkinsonism. Following the observation of higher risk of PD in patients affected by Gaucher disease, a lysosomal disorder caused by mutations in the glucocerebrosidase (GBA) gene, it was discovered that mutations in this gene constitute the single largest risk factor for development of idiopathic PD. Patients with PD and GBA mutations are clinically indistinguishable from patients with idiopathic PD, although some characteristics emerge depending on the specific mutation, such as slightly earlier onset...
October 2018: Neuroscientist: a Review Journal Bringing Neurobiology, Neurology and Psychiatry
Maja Di Rocco, Livia Pisciotta, Annalisa Madeo, Marta Bertamino, Stefano Bertolini
BACKGROUND: 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...
January 27, 2018: Orphanet Journal of Rare Diseases
Dominick Amato, Mary Anne Patterson
BACKGROUND: Intravenous enzyme replacement therapy is a first-line therapy for Gaucher disease type 1, and substrate reduction therapy represents an oral treatment alternative. Both enzyme replacement therapy and substrate reduction therapy are generally used as monotherapies in Gaucher disease. However, one randomized study and several case reports have described combination therapy over short time periods. CASE PRESENTATION: We report two female Gaucher disease type 1 patients of mainly Anglo-Saxon descent, where combined enzyme replacement therapy and miglustat substrate reduction therapy were administered to overcome refractory clinical symptoms...
January 27, 2018: Journal of Medical Case Reports
Kazuki Sawamoto, Hui-Hsuan Chen, Carlos J Alméciga-Díaz, Robert W Mason, Shunji Tomatsu
Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders (LSDs) caused by a deficiency of lysosomal enzymes, leading to a wide range of various clinical symptoms depending upon the type of MPS or its severity. Enzyme replacement therapy (ERT), hematopoietic stem cell transplantation (HSCT), substrate reduction therapy (SRT), and various surgical procedures are currently available for patients with MPS. However, there is no curative treatment for this group of disorders. Gene therapy should be a one-time permanent therapy, repairing the cause of enzyme deficiency...
February 2018: Molecular Genetics and Metabolism
David P W Rastall, Andrea Amalfitano
Purpose of review Lysosomal storage disorders (LSDs) are a class of genetic disorders that are a testing ground for the invention of novel therapeutics including enzyme replacement therapy (ERT), substrate reduction therapy (SRT), gene therapy, and hematopoietic stem cell transplant (HSCT). This review summarizes recently approved drugs, then examines the successful clinical trials in gene therapy and HSCT. Recent findings The FDA has recently approved a second SRT by reversing an earlier FDA decision, suggesting a favorable regulatory landscape going forward...
November 4, 2017: Current Treatment Options in Neurology
Bushra Afroze, Nick Brown
The lysosomal storage diseases are a group of rare, inherited metabolic diseases affecting about 1 in 7000 to 8000 people. In recent years, the introduction of enzyme replacement therapy, substrate reduction therapy and small molecule therapy, has changed the natural course of this otherwise progressive group of disorders leading to severe morbidity and early mortality. These treatment options, however, are extremely expensive and are needed for life thus presenting an economical as well as ethical challenge to the affected families and the health care system of a country...
July 2017: Pakistan Journal of Medical Sciences Quarterly
Fabiano Poswar, Guilherme Baldo, Roberto Giugliani
The mucopolysaccharidoses are lysosomal diseases characterized by deficient activity of one of the enzymes that degrades glycosaminoglycans. Treatment options are limited; therefore, new treatments are under investigation. Areas covered: We review the medicinal products for the treatment of mucopolysaccharidoses that are currently being investigated in phase I and phase II clinical trials. Expert opinion: The number of alternatives to treat MPS diseases increased dramatically in an attempt to provide therapy options for orphan MPS diseases and to address the unmet needs of the MPS that already have a treatment available...
December 2017: Expert Opinion on Investigational Drugs
Usha R Somaraju, Krishna Tadepalli
BACKGROUND: Gaucher disease is the most common lysosomal storage disorder caused by a deficiency of the enzyme glucocerebrosidase. Current treatment of the disease involves a choice from enzyme replacement therapy, substrate reduction therapy and hemotopoietic stem cell transplantation (HSCT). HSCT is a high risk procedure with possible long-term benefits in the regression of skeletal and neurological changes in people with Gaucher disease. This is an update of a previously published Cochrane Review...
October 18, 2017: Cochrane Database of Systematic Reviews
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