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      Comparative Analysis of Acid Sphingomyelinase Distribution in the CNS of Rats and Mice Following Intracerebroventricular Delivery

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          Abstract

          Niemann-Pick A (NPA) disease is a lysosomal storage disorder (LSD) caused by a deficiency in acid sphingomyelinase (ASM) activity. Previously, we reported that biochemical and functional abnormalities observed in ASM knockout (ASMKO) mice could be partially alleviated by intracerebroventricular (ICV) infusion of hASM. We now show that this route of delivery also results in widespread enzyme distribution throughout the rat brain and spinal cord. However, enzyme diffusion into CNS parenchyma did not occur in a linear dose-dependent fashion. Moreover, although the levels of hASM detected in the rat CNS were determined to be within the range shown to be therapeutic in ASMKO mice, the absolute amounts represented less than 1% of the total dose administered. Finally, our results also showed that similar levels of enzyme distribution are achieved across rodent species when the dose is normalized to CNS weight as opposed to whole body weight. Collectively, these data suggest that the efficacy observed following ICV delivery of hASM in ASMKO mice could be scaled to CNS of the rat.

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          Enzyme replacement therapy in Fabry disease: a randomized controlled trial.

          R Schiffmann, J. B. Kopp, H Austin … (2001)
          Fabry disease is a metabolic disorder without a specific treatment, caused by a deficiency of the lysosomal enzyme alpha-galactosidase A (alpha-gal A). Most patients experience debilitating neuropathic pain and premature mortality because of renal failure, cardiovascular disease, or cerebrovascular disease. To evaluate the safety and efficacy of intravenous alpha-gal A for Fabry disease. Double-blind placebo-controlled trial conducted from December 1998 to August 1999 at the Clinical Research Center of the National Institutes of Health. Twenty-six hemizygous male patients, aged 18 years or older, with Fabry disease that was confirmed by alpha-gal A assay. A dosage of 0.2 mg/kg of alpha-gal A, administered intravenously every other week (12 doses total). Effect of therapy on neuropathic pain while without neuropathic pain medications measured by question 3 of the Brief Pain Inventory (BPI). Mean (SE) BPI neuropathic pain severity score declined from 6.2 (0.46) to 4.3 (0.73) in patients treated with alpha-gal A vs no significant change in the placebo group (P =.02). Pain-related quality of life declined from 3.2 (0.55) to 2.1 (0.56) for patients receiving alpha-gal A vs 4.8 (0.59) to 4.2 (0.74) for placebo (P =.05). In the kidney, glomeruli with mesangial widening decreased by a mean of 12.5% for patients receiving alpha-gal vs a 16.5% increase for placebo (P =.01). Mean inulin clearance decreased by 6.2 mL/min for patients receiving alpha-gal A vs 19.5 mL/min for placebo (P =.19). Mean creatinine clearance increased by 2.1 mL/min (0.4 mL/s) for patients receiving alpha-gal A vs a decrease of 16.1 mL/min (0.3 mL/s) for placebo (P =.02). In patients treated with alpha-gal A, there was an approximately 50% reduction in plasma glycosphingolipid levels, a significant improvement in cardiac conduction, and a significant increase in body weight. Intravenous infusions of alpha-gal A are safe and have widespread therapeutic efficacy in Fabry disease.
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            Replacement therapy for inherited enzyme deficiency--macrophage-targeted glucocerebrosidase for Gaucher's disease.

            N Barton, R O Brady, J Dambrosia … (1991)
            Gaucher's disease, the most prevalent of the sphingolipid storage disorders, is caused by a deficiency of the enzyme glucocerebrosidase (glucosylceramidase). Enzyme replacement was proposed as a therapeutic strategy for this disorder in 1966. To assess the clinical effectiveness of this approach, we infused macrophage-targeted human placental glucocerebrosidase (60 IU per kilogram of body weight every 2 weeks for 9 to 12 months) into 12 patients with type 1 Gaucher's disease who had intact spleens. The frequency of infusions was increased to once a week in two patients (children) during part of the trial because they had clinically aggressive disease. The hemoglobin concentration increased in all 12 patients, and the platelet count in 7. Serum acid phosphatase activity decreased in 10 patients during the trial, and the plasma glucocerebroside level in 9. Splenic volume decreased in all patients after six months of treatment, and hepatic volume in five. Early signs of skeletal improvements were seen in three patients. The enzyme infusions were well tolerated, and no antibody to the exogenous enzyme developed. Intravenous administration of macrophage-targeted glucocerebrosidase produces objective clinical improvement in patients with type 1 Gaucher's disease. The hematologic and visceral responses to enzyme replacement develop more rapidly than the skeletal response.
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              Enzyme-replacement therapy in mucopolysaccharidosis I.

              I Walot, M Passage, Nicole R Hoft … (2001)
              Mucopolysaccharidosis I is a lysosomal storage disease caused by a deficiency of the enzyme alpha-L-iduronidase. We evaluated the effect of enzyme-replacement therapy with recombinant human alpha-L-iduronidase in patients with this disorder. We treated 10 patients with mucopolysaccharidosis I (age, 5 to 22 years) with recombinant human alpha-L-iduronidase at a dose of 125,000 U per kilogram of body weight given intravenously once weekly for 52 weeks. The patients were evaluated at base line and at 6, 12, 26, and 52 weeks by detailed clinical examinations, magnetic resonance imaging of the abdomen and brain, echocardiography, range-of-motion measurements, polysomnography, clinical laboratory evaluations, measurements of leukocyte alpha-L-iduronidase activity, and urinary glycosaminoglycan excretion. Hepatosplenomegaly decreased significantly in all patients, and the size of the liver was normal for body weight and age in eight patients by 26 weeks. The rate of growth in height and weight increased by a mean of 85 and 131 percent, respectively, in the six prepubertal patients. The mean maximal range of motion of shoulder flexion and elbow extension increased significantly. The number of episodes of apnea and hypopnea during sleep decreased 61 percent. New York Heart Association functional class improved by one or two classes in all patients. Urinary glycosaminoglycan excretion decreased after 3 to 4 weeks of treatment; the mean reduction was 63 percent of base-line values. Five patients had transient urticaria during infusions. Serum antibodies to alpha-L-iduronidase were detected in four patients. In patients with mucopolysaccharidosis I, treatment with recombinant human alpha-L-iduronidase reduces lysosomal storage in the liver and ameliorates some clinical manifestations of the disease.
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                Author and article information

                Contributors
                : Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2011
                Publication date (Electronic): 25 January 2011
                Volume: 6
                Issue: 1
                Electronic Location Identifier: e16313
                Affiliations
                [1]Genzyme Corporation, Framingham, Massachusetts, United States of America
                Brigham and Women's Hospital, Harvard Medical School, United States of America
                Author notes

                Conceived and designed the experiments: LSS SHC JCD. Performed the experiments: CMT TJT JAF TVT JCD. Analyzed the data: CMT TJT JCD. Wrote the paper: SHC JCD.

                Article
                Publisher ID: PONE-D-10-03351
                DOI: 10.1371/journal.pone.0016313
                PMC ID: 3026829
                PubMed ID: 21283548
                SO-VID: 40b1c3ad-3b08-44f6-a94a-aa9f6b4eb964
                Copyright © Treleaven et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                Date received : 30 September 2010
                Date accepted : 9 December 2010
                Page count
                Pages: 7
                Categories
                Subject: Research Article
                Subject: Biology
                Subject: Biochemistry
                Subject: Lipids
                Subject: Lipid Metabolism
                Subject: Sphingolipids
                Subject: Drug Discovery
                Subject: Enzymes
                Subject: Immunochemistry
                Subject: Metabolism
                Subject: Biotechnology
                Subject: Drug Discovery
                Subject: Neuroscience
                Subject: Neural Homeostasis
                Subject: Neurobiology of Disease and Regeneration
                Subject: Medicine
                Subject: Anatomy and Physiology
                Subject: Neurological System
                Subject: Central Nervous System
                Subject: Nerve Tissue
                Subject: Nervous System Components
                Subject: Nervous System Physiology
                Subject: Neural Homeostasis
                Subject: Fluid Physiology
                Subject: Drugs and Devices
                Subject: Drug Research and Development
                Subject: Drug Discovery
                Subject: Metabolic Disorders
                Subject: Niemann-Pick disease
                Subject: Neurology
                Subject: Neurodegenerative Diseases

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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