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Frances M Platt - One of the best experts on this subject based on the ideXlab platform.
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Substrate Reduction Therapy
Acta Paediatrica, 2020Co-Authors: Frances M Platt, Mylvaganam JeyakumarAbstract:UNLABELLED: The therapeutic options for lysosomal storage diseases (LSDs) have expanded greatly over the past decade, although for many disorders there is still no effective treatment. Given that the majority of LSDs involve pathological changes in both the brain and peripheral tissues, effective treatment of central nervous system (CNS) and peripheral manifestations still remains a considerable technical challenge. Type 1 Gaucher disease has two approved treatment modalities - enzyme replacement Therapy (ERT) and Substrate Reduction Therapy (SRT) - which have unique, independent and potentially complementary mechanisms of action. The availability of these two therapies has greatly increased the options for the effective clinical management of type 1 Gaucher disease. ERT involves the intravenous administration of fully functional enzyme that is taken up by cells and delivered to the lysosome, where it can compensate for the underlying enzyme deficiency. SRT uses an orally available, small molecule drug that inhibits the first committed step in glycosphingolipid biosynthesis. The aim is to reduce the rate of biosynthesis of glycosphingolipids to offset the catabolic defect, restoring the balance between the rate of biosynthesis and the rate of catabolism. SRT also has the potential to treat LSDs with CNS pathology, as the drug in clinical use (miglustat, Zavesca; Actelion Pharmaceuticals Ltd, Allschwil, Switzerland) crosses the blood-brain barrier. In this review, the current status of SRT for the treatment of Gaucher disease and other LSDs will be discussed, based upon preclinical and clinical studies. CONCLUSION: SRT is an oral alternative treatment option for patients with type 1 Gaucher disease unwilling or unable to receive ERT. With the recent reports of clinical improvement/stabilization of CNS manifestations following SRT in patients with Niemann-Pick disease type C, miglustat may also have a role to play in the management of patients with glycosphingolipid storage in the brain. Furthermore, as SRT synergises with other therapeutic modalities, it may also prove to be a key component of combination therapies in the future
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Lucerastat, an iminosugar for Substrate Reduction Therapy in Fabry disease: preclinical evidence
Molecular Genetics and Metabolism, 2020Co-Authors: Richard W.d. Welford, Frances M Platt, Andreas Mühlemann, David Priestman, Marco Garzotti, Caroline Deymier, Eric A Ertel, Marc Iglarz, Daniela Baldoni, Markus R. ProbstAbstract:Fabry disease (FD) is a lysosomal disorder caused by mutations in the GLA gene coding for α‑galactosidase A (α‑GalA). These mutations lead to the accumulation of α‑GalA Substrates, including globotriaosylceramide (Gb3). As a consequence of lipid storage, Fabry patients can suffer from neuropathic pain, impaired kidney function and cardiomyopathy. Existing treatments for FD either require bi-weekly intravenous infusions of replacement enzyme, or are effective in a limited number of patients with specific “amenable” mutations. Substrate Reduction Therapy (SRT) with lucerastat, an orally-available small molecule inhibitor of glucosylceramide synthase (GCS) to reduce Gb3 accumulation is an alternative mechanism, that would be suitable for all FD patients
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Substrate Reduction Therapy
Lysosomal Storage Disorders, 2020Co-Authors: Frances M Platt, Terry D ButtersAbstract:The glycosphingolipidoses are a family of storage diseases that arise due to incomplete catabolism of glycosphingolipids (GSLs) in the lysosome (Wraith, 2002). The majority are autosomal recessive disorders and result from mutations in the genes that encode the catabolic enzymes of the lysosome (Winchester, 2004). Clinically they are highly variable (Beck, 2001) but typically have a neurodegenerative course and commonly present in infancy or early childhood (Wraith, 2004). Adult-onset variants also occur (Rapola, 1994; Wraith, 2004). The age of onset is influenced by the residual enzyme activity present, that in turn reflects the impact a specific mutation has on the properties of the enzyme (Rapola, 1994; Winchester, 2004). Little or no activity leads to rapid storage and early onset of symptoms whereas higher levels of residual activity lead to a slower rate of storage and a longer presymptomatic period. In this chapter, we focus on a drug-based Therapy that is relevant to all lysosomal diseases involving the storage of glucosylceramidederived GSLs, including Gaucher, Fabry, Tay-Sachs, Sandhoff, and GM1 gangliosidosis. In addition, storage diseases involving the secondary storage of GSL
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beneficial effects of Substrate Reduction Therapy in a mouse model of gm1 gangliosidosis
Molecular Genetics and Metabolism, 2008Co-Authors: Elena Elliotsmith, Mylvaganam Jeyakumar, Raymond A Dwek, Terry D Butters, Anneliese O Speak, Emyr Lloydevans, David Smith, Aarnoud C Van Der Spoel, Alessandra Dazzo, Frances M PlattAbstract:Abstract GM1 gangliosidosis is an inherited neurodegenerative disorder caused by lysosomal β-galactosidase deficiency, resulting in the storage of GM1 and GA1, primarily in the central nervous system. This disease typically afflicts infants and young children and there is currently no effective Therapy. Substrate Reduction Therapy (SRT) could be of potential benefit. The imino sugars N -butyldeoxynojirimycin ( N B-DNJ, miglustat, Zavesca™) and N -butyldeoxygalactonojirimycin ( N B-DGJ) used for SRT inhibit glucosylceramide synthase (GlcCerS) that catalyses the first committed step in glycosphingolipid biosynthesis. We have compared the efficacy and tolerability of N B-DNJ and N B-DGJ in the β-galactosidase knockout mouse. N B-DGJ was better tolerated than N B-DNJ, due to intrinsic gastrointestinal tract dysfunction that was exacerbated by N B-DNJ. However, functional improvement was greatest with N B-DNJ treatment which may potentially be caused by novel anti-inflammatory properties of N B-DNJ.
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Imino sugar inhibitors for treating the lysosomal glycosphingolipidoses
Glycobiology, 2005Co-Authors: Terry D Butters, Raymond A Dwek, Frances M PlattAbstract:The inherited metabolic disorders of glycosphingolipid (GSL) metabolism are a relatively rare group of diseases that have diverse and often neurodegenerative phenotypes. Typically, a deficiency in catabolic enzyme activity leads to lysosomal storage of GSL Substrates and in many diseases, several other glycoconjugates. A novel generic approach to treating these diseases has been termed Substrate Reduction Therapy (SRT), and the discovery and development of N-alkylated imino sugars as effective and approved drugs is discussed. An understanding of the molecular mechanism for the inhibition of the key enzyme in GSL biosynthesis, ceramide glucosyltransferase (CGT) by N-alkylated imino sugars, has also lead to compound design for improvements to inhibitory potency, bioavailability, enzyme selectivity, and biological safety. Following a successful clinical evaluation of one compound, N-butyl-deoxynojirimycin [(NB-DNJ), miglustat, Zavesca], for treating type I Gaucher disease, issues regarding the significance of side effects and CNS access have been addressed as exposure of drug to patients has increased. An alternative experimental approach to treat specific glycosphingolipid (GSL) lysosomal storage diseases is to use imino sugars as molecular chaperons that assist protein folding and stability of mutant enzymes. The principles of chaperon-mediated Therapy (CMT) are described, and the potential efficacy and preclinical status of imino sugars is compared with Substrate Reduction Therapy (SRT). The increasing use of imino sugars for clinical evaluation of a group of storage diseases that are complex and often intractable disorders to treat has considerable benefit. This is particularly so given the ability of small molecules to be orally available, penetrate the central nervous system (CNS), and have well-characterized biological and pharmacological properties.
Terry D Butters - One of the best experts on this subject based on the ideXlab platform.
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Substrate Reduction Therapy
Lysosomal Storage Disorders, 2020Co-Authors: Frances M Platt, Terry D ButtersAbstract:The glycosphingolipidoses are a family of storage diseases that arise due to incomplete catabolism of glycosphingolipids (GSLs) in the lysosome (Wraith, 2002). The majority are autosomal recessive disorders and result from mutations in the genes that encode the catabolic enzymes of the lysosome (Winchester, 2004). Clinically they are highly variable (Beck, 2001) but typically have a neurodegenerative course and commonly present in infancy or early childhood (Wraith, 2004). Adult-onset variants also occur (Rapola, 1994; Wraith, 2004). The age of onset is influenced by the residual enzyme activity present, that in turn reflects the impact a specific mutation has on the properties of the enzyme (Rapola, 1994; Winchester, 2004). Little or no activity leads to rapid storage and early onset of symptoms whereas higher levels of residual activity lead to a slower rate of storage and a longer presymptomatic period. In this chapter, we focus on a drug-based Therapy that is relevant to all lysosomal diseases involving the storage of glucosylceramidederived GSLs, including Gaucher, Fabry, Tay-Sachs, Sandhoff, and GM1 gangliosidosis. In addition, storage diseases involving the secondary storage of GSL
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beneficial effects of Substrate Reduction Therapy in a mouse model of gm1 gangliosidosis
Molecular Genetics and Metabolism, 2008Co-Authors: Elena Elliotsmith, Mylvaganam Jeyakumar, Raymond A Dwek, Terry D Butters, Anneliese O Speak, Emyr Lloydevans, David Smith, Aarnoud C Van Der Spoel, Alessandra Dazzo, Frances M PlattAbstract:Abstract GM1 gangliosidosis is an inherited neurodegenerative disorder caused by lysosomal β-galactosidase deficiency, resulting in the storage of GM1 and GA1, primarily in the central nervous system. This disease typically afflicts infants and young children and there is currently no effective Therapy. Substrate Reduction Therapy (SRT) could be of potential benefit. The imino sugars N -butyldeoxynojirimycin ( N B-DNJ, miglustat, Zavesca™) and N -butyldeoxygalactonojirimycin ( N B-DGJ) used for SRT inhibit glucosylceramide synthase (GlcCerS) that catalyses the first committed step in glycosphingolipid biosynthesis. We have compared the efficacy and tolerability of N B-DNJ and N B-DGJ in the β-galactosidase knockout mouse. N B-DGJ was better tolerated than N B-DNJ, due to intrinsic gastrointestinal tract dysfunction that was exacerbated by N B-DNJ. However, functional improvement was greatest with N B-DNJ treatment which may potentially be caused by novel anti-inflammatory properties of N B-DNJ.
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Substrate Reduction Therapy in the infantile form of tay sachs disease
Neurology, 2006Co-Authors: Bruno Bembi, F Marchetti, V I Guerci, Giovanni Ciana, R Addobbati, Domenico Leonardo Grasso, Rita Barone, R Cariati, L Fernandezguillen, Terry D ButtersAbstract:Substrate Reduction Therapy (SRT) with miglustat has been proposed for treatment of some lysosomal storage disorders. Based on the positive experience in Gaucher disease and experimental data in Tay-Sachs (TSD) and Sandhoff animal models, the authors investigated the clinical efficacy of SRT in two patients with infantile TSD. SRT could not arrest the patients9 neurologic deterioration. However, a significant drug concentration in CSF as well as macrocephaly prevention were observed.
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Imino sugar inhibitors for treating the lysosomal glycosphingolipidoses
Glycobiology, 2005Co-Authors: Terry D Butters, Raymond A Dwek, Frances M PlattAbstract:The inherited metabolic disorders of glycosphingolipid (GSL) metabolism are a relatively rare group of diseases that have diverse and often neurodegenerative phenotypes. Typically, a deficiency in catabolic enzyme activity leads to lysosomal storage of GSL Substrates and in many diseases, several other glycoconjugates. A novel generic approach to treating these diseases has been termed Substrate Reduction Therapy (SRT), and the discovery and development of N-alkylated imino sugars as effective and approved drugs is discussed. An understanding of the molecular mechanism for the inhibition of the key enzyme in GSL biosynthesis, ceramide glucosyltransferase (CGT) by N-alkylated imino sugars, has also lead to compound design for improvements to inhibitory potency, bioavailability, enzyme selectivity, and biological safety. Following a successful clinical evaluation of one compound, N-butyl-deoxynojirimycin [(NB-DNJ), miglustat, Zavesca], for treating type I Gaucher disease, issues regarding the significance of side effects and CNS access have been addressed as exposure of drug to patients has increased. An alternative experimental approach to treat specific glycosphingolipid (GSL) lysosomal storage diseases is to use imino sugars as molecular chaperons that assist protein folding and stability of mutant enzymes. The principles of chaperon-mediated Therapy (CMT) are described, and the potential efficacy and preclinical status of imino sugars is compared with Substrate Reduction Therapy (SRT). The increasing use of imino sugars for clinical evaluation of a group of storage diseases that are complex and often intractable disorders to treat has considerable benefit. This is particularly so given the ability of small molecules to be orally available, penetrate the central nervous system (CNS), and have well-characterized biological and pharmacological properties.
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improved outcome of n butyldeoxygalactonojirimycin mediated Substrate Reduction Therapy in a mouse model of sandhoff disease
Neurobiology of Disease, 2004Co-Authors: Ulrika Andersson, Mylvaganam Jeyakumar, Raymond A Dwek, Terry D Butters, David Smith, Mario Cortina Borja, Frances M PlattAbstract:Abstract Sandhoff disease is a severe neurodegenerative glycosphingolipid (GSL) lysosomal storage disorder, currently without treatment options. One therapeutic approach under investigation is Substrate Reduction Therapy (SRT). By partially inhibiting GSL biosynthesis, the impaired rate of GSL catabolism is balanced by a slower rate of influx of GSLs into the lysosome. In a previous study, we reported the beneficial effects of treating Sandhoff disease mice with the glucose analogue N-butyldeoxynojirimycin (NB-DNJ), a compound that inhibits the first step of GSL biosynthesis catalysed by the ceramide specific glucosyltransferase. NB-DNJ, however, exhibits adverse effects at high doses such as weight loss and GI tract distress (due to glucosidase inhibition). This might limit the therapeutic potential of NB-DNJ for treating diseases affecting the CNS where high dose Therapy may be required to achieve therapeutic levels of the drug in the brain. In the present study, a more selective compound, the galactose analogue N-butyldeoxygalactonojirimycin (NB-DGJ), was evaluated in the Sandhoff disease mouse model. Treatment with NB-DGJ showed greater therapeutic efficacy than NB-DNJ with no detectable side effects. The ability to escalate the dose of NB-DGJ, leading to extended life expectancy and increased delay in symptom onset, demonstrates the greater therapeutic potential of NB-DGJ for the treatment of the human gangliosidoses.
Johannes M F G Aerts - One of the best experts on this subject based on the ideXlab platform.
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biochemical response to Substrate Reduction Therapy versus enzyme replacement Therapy in gaucher disease type 1 patients
Orphanet Journal of Rare Diseases, 2016Co-Authors: Bouwien E Smid, Carla E M Hollak, Maria J Ferraz, Marri Verhoek, Mina Mirzaian, Patrick Wisse, Herman S Overkleeft, Johannes M F G AertsAbstract:Background We retrospectively compared biochemical responses in type 1 Gaucher disease patients to treatment with glycosphingolipid synthesis inhibitors miglustat and eliglustat and ERT.
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Iminosugar-based inhibitors of glucosylceramide synthase increase brain glycosphingolipids and survival in a mouse model of Sandhoff disease
PLOS ONE, 2011Co-Authors: Karen M Ashe, Johannes M F G Aerts, Jennifer B Nietupski, Dinesh S Bangari, Lingyun Li, Mario A. Cabrera-salazar, Scott D. Bercury, Christopher G.f. Cooper, Diane P CopelandAbstract:The neuropathic glycosphingolipidoses are a subgroup of lysosomal storage disorders for which there are no effective therapies. A potential approach is Substrate Reduction Therapy using inhibitors of glucosylceramide synthase (GCS) to decrease the synthesis of glucosylceramide and related glycosphingolipids that accumulate in the lysosomes. Genz-529468, a blood-brain barrier-permeant iminosugar-based GCS inhibitor, was used to evaluate this concept in a mouse model of Sandhoff disease, which accumulates the glycosphingolipid GM2 in the visceral organs and CNS. As expected, oral administration of the drug inhibited hepatic GM2 accumulation. Paradoxically, in the brain, treatment resulted in a slight increase in GM2 levels and a 20-fold increase in glucosylceramide levels. The increase in brain glucosylceramide levels might be due to concurrent inhibition of the non-lysosomal glucosylceramidase, Gba2. Similar results were observed with NB-DNJ, another iminosugar-based GCS inhibitor. Despite these unanticipated increases in glycosphingolipids in the CNS, treatment nevertheless delayed the loss of motor function and coordination and extended the lifespan of the Sandhoff mice. These results suggest that the CNS benefits observed in the Sandhoff mice might not necessarily be due to Substrate Reduction Therapy but rather to off-target effects.
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potential efficacy of enzyme replacement and Substrate Reduction Therapy in three siblings with gaucher disease type iii
Journal of Inherited Metabolic Disease, 2008Co-Authors: J Coxbrinkman, Carla E M Hollak, M J Van Breemen, B T Van Maldegem, L Bour, W E Donker, Frits A Wijburg, Johannes M F G AertsAbstract:We report three siblings with Gaucher disease type III, born between 1992 and 2004. During this period, new developments resulted in different potential therapies, changing clinical practice. The two eldest siblings received enzyme replacement Therapy (ERT) from the age of 24 and 5 months respectively, later followed by an increase in dosage. ERT was combined with Substrate Reduction Therapy (SRT) from the ages of 12 and 8 years, respectively. In the youngest sibling the combination of high-dose ERT and SRT was given from the age of 5 months. The two eldest siblings showed significant neurological impairment from the age of 1.5 years, starting with a convergent strabismus and partial oculomotor apraxia, followed by cognitive decline and an abnormal EEG and BAER. In contrast, the neurological development in the youngest sibling is almost completely normal. At the age of 3 years, cognitive development, EEG and BAER are all normal. Disturbed saccadic eye movements, which were already present at the start of Therapy, remained stable. In addition to the clinical efficacy, we report on the biochemical response to Therapy. Based on our results, the combination of high-dose ERT and SRT should be considered as a possible therapeutic approach for GD III, especially if started at a young age. Further follow-up studies are necessary to explore the long-term therapeutic effects.
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Substrate Reduction Therapy of glycosphingolipid storage disorders
Journal of Inherited Metabolic Disease, 2006Co-Authors: Johannes M F G Aerts, Carla E M Hollak, Rolf G Boot, Johanna E M Groener, Mario MaasAbstract:In the last 15 years enormous progress has been made regarding Therapy of type I Gaucher disease, a severely disabling disorder characterized by intralysosomal storage of glucosylceramide in tissue macrophages. Effective enzyme replacement Therapy of type I Gaucher disease, based on chronic intravenous administration of mannose-terminated recombinant human glucocerebrosidase, has been available since 1990 and has been applied in several thousand patients without serious adverse effects. An alternative therapeutic approach, so-called Substrate Reduction Therapy, is based on partial Reduction of the synthesis of glucosylceramide and hence of subsequent metabolites. Oral administration of an inhibitor of glucosylceramide synthesis (N-butyldeoxynojirimycin, registered in Europe since 2002 as miglustat (Zavesca)), is effective in reversing clinical symptoms in type I Gaucher patients with mild to moderate disease manifestations. The growing long-term experience with Substrate Reduction Therapy indicates that this treatment is also without major adverse effects. Substrate Reduction Therapy, in conjunction with enzyme replacement Therapy, may play an important role in the future clinical management of patients suffering from type I Gaucher disease. Clinical trials are under way that should reveal the value of Substrate Reduction for maintenance Therapy of type I Gaucher disease and for treatment of neuronopathic variants of Gaucher disease, Niemann–Pick disease type C, late-onset Tay–Sachs disease and Sandhoff disease.
Seng H Cheng - One of the best experts on this subject based on the ideXlab platform.
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efficacy of enzyme and Substrate Reduction Therapy with a novel antagonist of glucosylceramide synthase for fabry disease
Molecular Medicine, 2015Co-Authors: Karen M Ashe, Jennifer B Nietupski, Dinesh S Bangari, Bing Wang, Eva Budman, Craig S Siegel, Robert J Desnick, Ronald K Scheule, John P Leonard, Seng H ChengAbstract:Fabry disease, an X-linked glycosphingolipid storage disorder, is caused by the deficient activity of α-galactosidase A (α-Gal A). This results in the lysosomal accumulation in various cell types of its glycolipid Substrates, including globotriaosylceramide (GL-3) and lysoglobotriaosylceramide (globotriaosyl lysosphingolipid, lyso-GL-3), leading to kidney, heart, and cerebrovascular disease. To complement and potentially augment the current standard of care, biweekly infusions of recombinant α-Gal A, the merits of Substrate Reduction Therapy (SRT) by selectively inhibiting glucosylceramide synthase (GCS) were examined. Here, we report the development of a novel, orally available GCS inhibitor (Genz-682452) with pharmacological and safety profiles that have potential for treating Fabry disease. Treating Fabry mice with Genz-682452 resulted in reduced tissue levels of GL-3 and lyso-GL-3 and a delayed loss of the thermal nociceptive response. Greatest improvements were realized when the therapeutic intervention was administered to younger mice before they developed overt pathology. Importantly, as the pharmacologic profiles of α-Gal A and Genz-682452 are different, treating animals with both drugs conferred the greatest efficacy. For example, because Genz-682452, but not α-Gal A, can traverse the blood–brain barrier, levels of accumulated glycosphingolipids were reduced in the brain of Genz-682452–treated but not α-Gal A–treated mice. These results suggest that combining Substrate Reduction and enzyme replacement may confer both complementary and additive therapeutic benefits in Fabry disease.
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antisense oligonucleotide mediated suppression of muscle glycogen synthase 1 synthesis as an approach for Substrate Reduction Therapy of pompe disease
Molecular therapy. Nucleic acids, 2014Co-Authors: Nicholas P Clayton, Ronald K Scheule, Seng H Cheng, Carol A Nelson, Timothy E Weeden, Kristin M Taylor, Rodney J Moreland, Lucy Phillips, Andrew Leger, Bruce M WentworthAbstract:Pompe disease is an autosomal recessive disorder caused by a deficiency of acid α-glucosidase (GAA; EC 3.2.1.20) and the resultant progressive lysosomal accumulation of glycogen in skeletal and cardiac muscles. Enzyme replacement Therapy using recombinant human GAA (rhGAA) has proven beneficial in addressing several aspects of the disease such as cardiomyopathy and aberrant motor function. However, residual muscle weakness, hearing loss, and the risks of arrhythmias and osteopenia persist despite enzyme Therapy. Here, we evaluated the relative merits of Substrate Reduction Therapy (by inhibiting glycogen synthesis) as a potential adjuvant strategy. A phosphorodiamidate morpholino oligonucleotide (PMO) designed to invoke exon skipping and premature stop codon usage in the transcript for muscle specific glycogen synthase (Gys1) was identified and conjugated to a cell penetrating peptide (GS-PPMO) to facilitate PMO delivery to muscle. GS-PPMO systemic administration to Pompe mice led to a dose-dependent decrease in glycogen synthase transcripts in the quadriceps, and the diaphragm but not the liver. An mRNA response in the heart was seen only at the higher dose tested. Associated with these decreases in transcript levels were correspondingly lower tissue levels of muscle specific glycogen synthase and activity. Importantly, these Reductions resulted in significant decreases in the aberrant accumulation of lysosomal glycogen in the quadriceps, diaphragm, and heart of Pompe mice. Treatment was without any overt toxicity, supporting the notion that Substrate Reduction by GS-PPMO-mediated inhibition of muscle specific glycogen synthase represents a viable therapeutic strategy for Pompe disease after further development.
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Enzyme Replacement and Pharmacologic Chaperone Therapies for Lysomal Storage Disease
Reference Module in Biomedical Sciences, 2014Co-Authors: Robert J Desnick, Edward H. Schuchman, Kenneth H. Astrin, Seng H ChengAbstract:Over the past 20 years, significant progress has been made in the development of therapies for the group of disorders referred to collectively as the lysosomal storage diseases. This development is born of an increasing understanding of the biology and molecular bases underlying these inborn errors of metabolism and of emerging technologies that could be brought to bear in the management of their clinical manifestations. At present, patients with several of these lysosomal storage disorders are effectively managed by enzyme replacement or Substrate Reduction Therapy. Additionally, other therapeutic paradigms are emerging, which if successful will add to the repertoire of treatments for this group of diseases.
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improved management of lysosomal glucosylceramide levels in a mouse model of type 1 gaucher disease using enzyme and Substrate Reduction Therapy
Journal of Inherited Metabolic Disease, 2010Co-Authors: John Marshall, Craig S Siegel, Ronald K Scheule, Kerry Anne Mceachern, Wei Lien Chuang, Elizabeth Hutto, James A Shayman, Greg Grabowski, Diane P Copeland, Seng H ChengAbstract:Gaucher disease is caused by a deficiency of the lysosomal enzyme glucocerebrosidase (acid β-glucosidase), with consequent cellular accumulation of glucosylceramide (GL-1). The disease is managed by intravenous administrations of recombinant glucocerebrosidase (imiglucerase), although symptomatic patients with mild to moderate type 1 Gaucher disease for whom enzyme replacement Therapy (ERT) is not an option may also be treated by Substrate Reduction Therapy (SRT) with miglustat. To determine whether the sequential use of both ERT and SRT may provide additional benefits, we compared the relative pharmacodynamic efficacies of separate and sequential therapies in a murine model of Gaucher disease (D409V/null). As expected, ERT with recombinant glucocerebrosidase was effective in reducing the burden of GL-1 storage in the liver, spleen, and lung of 3-month-old Gaucher mice. SRT using a novel inhibitor of glucosylceramide synthase (Genz-112638) was also effective, albeit to a lesser degree than ERT. Animals administered recombinant glucocerebrosidase and then Genz-112638 showed the lowest levels of GL-1 in all the visceral organs and a reduced number of Gaucher cells in the liver. This was likely because the additional deployment of SRT following enzyme Therapy slowed the rate of reaccumulation of GL-1 in the affected organs. Hence, in patients whose disease has been stabilized by intravenously administered recombinant glucocerebrosidase, orally administered SRT with Genz-112638 could potentially be used as a convenient maintenance Therapy. In patients naive to treatment, ERT followed by SRT could potentially accelerate clearance of the offending Substrate.
Carla E M Hollak - One of the best experts on this subject based on the ideXlab platform.
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biochemical response to Substrate Reduction Therapy versus enzyme replacement Therapy in gaucher disease type 1 patients
Orphanet Journal of Rare Diseases, 2016Co-Authors: Bouwien E Smid, Carla E M Hollak, Maria J Ferraz, Marri Verhoek, Mina Mirzaian, Patrick Wisse, Herman S Overkleeft, Johannes M F G AertsAbstract:Background We retrospectively compared biochemical responses in type 1 Gaucher disease patients to treatment with glycosphingolipid synthesis inhibitors miglustat and eliglustat and ERT.
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enzyme replacement and Substrate Reduction Therapy for gaucher disease
Cochrane Database of Systematic Reviews, 2015Co-Authors: Elad Shemesh, Carla E M Hollak, Laura Deroma, Bruno Bembi, 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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The Cochrane Library - Enzyme replacement and Substrate Reduction Therapy for Gaucher disease
Cochrane Database of Systematic Reviews, 2015Co-Authors: Elad Shemesh, Carla E M Hollak, Laura Deroma, Bruno Bembi, 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 model disorder for biomarker discovery
Expert Review of Proteomics, 2009Co-Authors: Rolf G Boot, Carla E M Hollak, Mariëlle J. Van Breemen, Wouter Wegdam, Richard R. Sprenger, Shreyas M. De Jong, Dave Speijer, Laura Van Dussen, Huub C. J. Hoefsloot, Age K. SmildeAbstract:Gaucher disease is an inherited lysosomal storage disorder, characterized by massive accumulation of glucosylceramide-laden macrophages in the spleen, liver and bone marrow as a consequence of deficient activity of glucocerebrosidase. Gaucher disease has been the playground to develop new therapeutic interventions such as enzyme-replacement Therapy and Substrate-Reduction Therapy. The availability of these costly therapies has stimulated research regarding suitable biomarkers to monitor onset and progression of disease, as well as the efficacy of therapeutic intervention. Given the important role of storage cells in the pathology, various attempts have been made to identify proteins in plasma or serum reflecting the body burden of these pathological cells. In this review, the existing data regarding biomarkers for Gaucher disease, as well as the current application of biomarkers in clinical management of Gaucher patients are discussed. Moreover, the use of several modern proteomic technologies for the ide...
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potential efficacy of enzyme replacement and Substrate Reduction Therapy in three siblings with gaucher disease type iii
Journal of Inherited Metabolic Disease, 2008Co-Authors: J Coxbrinkman, Carla E M Hollak, M J Van Breemen, B T Van Maldegem, L Bour, W E Donker, Frits A Wijburg, Johannes M F G AertsAbstract:We report three siblings with Gaucher disease type III, born between 1992 and 2004. During this period, new developments resulted in different potential therapies, changing clinical practice. The two eldest siblings received enzyme replacement Therapy (ERT) from the age of 24 and 5 months respectively, later followed by an increase in dosage. ERT was combined with Substrate Reduction Therapy (SRT) from the ages of 12 and 8 years, respectively. In the youngest sibling the combination of high-dose ERT and SRT was given from the age of 5 months. The two eldest siblings showed significant neurological impairment from the age of 1.5 years, starting with a convergent strabismus and partial oculomotor apraxia, followed by cognitive decline and an abnormal EEG and BAER. In contrast, the neurological development in the youngest sibling is almost completely normal. At the age of 3 years, cognitive development, EEG and BAER are all normal. Disturbed saccadic eye movements, which were already present at the start of Therapy, remained stable. In addition to the clinical efficacy, we report on the biochemical response to Therapy. Based on our results, the combination of high-dose ERT and SRT should be considered as a possible therapeutic approach for GD III, especially if started at a young age. Further follow-up studies are necessary to explore the long-term therapeutic effects.
