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  1. Article ; Online: Combining angiotensin receptor blockade and enzyme replacement therapy for vascular disease in mucopolysaccharidosis type I

    Sarah C. Hurt / Moin U. Vera / Steven Q. Le / Shih-hsin Kan / Quang Bui / Patricia I. Dickson

    Molecular Genetics and Metabolism Reports, Vol 38, Iss , Pp 101036- (2024)

    1481  

    Abstract: Vascular involvement in the genetic disorder mucopolysaccharidosis type I (MPS I) has features of atherosclerotic disease near branch points of arterial vasculature, such as intimal thickening with disruption of the internal elastic lamina, and ... ...

    Abstract Vascular involvement in the genetic disorder mucopolysaccharidosis type I (MPS I) has features of atherosclerotic disease near branch points of arterial vasculature, such as intimal thickening with disruption of the internal elastic lamina, and proliferation of macrophages and myofibroblasts. Inflammatory pathways are implicated in the pathogenesis of vascular disease in MPS I animal models, evidenced by cytokines like CD18 and TGF-β within arterial plaques. The angiotensin II-mediated inflammatory pathway is well studied in human atherosclerotic coronary artery disease. Recent work indicates treatment with the angiotensin receptor blocker losartan may improve vascular MPS I disease in mouse models. Here, we combined losartan with the standard therapy for MPS I, enzyme replacement therapy (ERT), to measure effects on cytokines in serum and aortic vasculature. Each treatment group (losartan, ERT, and their combination) equally normalized levels of cytokines that were largely differential between normal and mutant mice. Some cytokines, notably CD30 ligand, Eotaxin-2, LIX, IL-13, IL-15, GM-CSF, MCP-5, MIG, and CCL3 showed elevations in mice treated with ERT above normal or mutant levels; these elevations were reduced or absent in mice that received losartan or combination therapy. The observations suggest that losartan may impact inflammatory cascades due to MPS I and may also blunt inflammation in combination with ERT.
    Keywords Lysosomal storage disease ; Hurler ; Scheie ; Hurler-Scheie ; Losartan ; Alpha-L-iduronidase ; Medicine (General) ; R5-920 ; Biology (General) ; QH301-705.5
    Subject code 610
    Language English
    Publishing date 2024-03-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Fatal COVID‐19 infection in a patient with long‐chain 3‐hydroxyacyl‐CoA dehydrogenase deficiency

    Parith Wongkittichote / James R. Watson / Jennifer M. Leonard / Elizabeth R. Toolan / Patricia I. Dickson / Dorothy K. Grange

    JIMD Reports, Vol 56, Iss 1, Pp 40-

    A case report

    2020  Volume 45

    Abstract: Abstract Long‐chain fatty‐acyl CoA dehydrogenase deficiency (LCHADD) is an inborn error of long chain fatty acid oxidation with various features including hypoketotic hypoglycemia, recurrent rhabdomyolysis, pigmentary retinopathy, peripheral neuropathy, ... ...

    Abstract Abstract Long‐chain fatty‐acyl CoA dehydrogenase deficiency (LCHADD) is an inborn error of long chain fatty acid oxidation with various features including hypoketotic hypoglycemia, recurrent rhabdomyolysis, pigmentary retinopathy, peripheral neuropathy, cardiomyopathy, and arrhythmias. Various stresses trigger metabolic decompensation. Coronavirus disease 2019 (COVID‐19) is a pandemic caused by the RNA virus SARS‐CoV‐2 with diverse presentations ranging from respiratory symptoms to myocarditis. We report a case of a patient with LCHADD who initially presented with typical metabolic decompensation symptoms including nausea, vomiting, and rhabdomyolysis in addition to mild cough, and was found to have COVID‐19. She developed acute respiratory failure and refractory hypotension from severe cardiomyopathy which progressed to multiple organ failure and death. Our case illustrates the need for close monitoring of cardiac function in patients with a long‐chain fatty acid oxidation disorder.
    Keywords cardiomyopathy ; COVID‐19 ; fatty acid oxidation disorder ; LCHAD ; long‐chain 3‐hydroxyacyl‐CoA dehydrogenase deficiency ; Diseases of the endocrine glands. Clinical endocrinology ; RC648-665 ; Genetics ; QH426-470 ; covid19
    Subject code 610
    Language English
    Publishing date 2020-11-01T00:00:00Z
    Publisher Wiley
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: A phase 1/2 open label nonrandomized clinical trial of intravenous 2-hydroxypropyl-β-cyclodextrin for acute liver disease in infants with Niemann-Pick C1

    Margaret Reynolds / Laura A. Linneman / Sofia Luna / Barbara B. Warner / Yumirle P. Turmelle / Sakil S. Kulkarni / Xuntian Jiang / Geetika Khanna / Marwan Shinawi / Forbes D. Porter / Daniel S. Ory / F. Sessions Cole / Patricia I. Dickson

    Molecular Genetics and Metabolism Reports, Vol 28, Iss , Pp 100772- (2021)

    2021  

    Abstract: Introduction: Niemann-Pick C (NPC) is an autosomal recessive disease due to defective NPC1 or NPC2 proteins resulting in endo-lysosomal storage of unesterified cholesterol in the central nervous system and liver. Acute liver disease in the newborn period ...

    Abstract Introduction: Niemann-Pick C (NPC) is an autosomal recessive disease due to defective NPC1 or NPC2 proteins resulting in endo-lysosomal storage of unesterified cholesterol in the central nervous system and liver. Acute liver disease in the newborn period may be self-limited or fatal. 2-hydroxypropyl-β-cyclodextrin (2HPBCD) is a cholesterol-binding agent that reduces lysosomal cholesterol storage. We have enrolled 3 infants 0–6 months old with direct hyperbilirubinemia due to NPC1 or NPC2 liver disease in a Phase I/II open label clinical trial of intravenous 2HPBCD. Methods: Infants received intravenous 2HPBCD twice a week for 6 weeks, followed by monthly infusion for 6-months. Primary outcome measure was reduction of plasma (3β,5α,6β-trihydroxy-cholan-24-oyl) glycine (TCG), a bile acid generated from cholesterol sequestered in lysosome. Results: Three participants completed this protocol. A fourth patient received intravenous 2HPBCD under an emergency investigational new drug study but later expired from her underlying condition. The three protocol patients are living and have improved liver enzymes and TCG. No patient has experienced a drug-related adverse event. Conclusion: Intravenous 2HPBCD was tolerated in three infants with liver disease due to NPC.
    Keywords Niemann Pick C ; Clinical trial ; 2-hydroxypropyl-β-cyclodextrin (2HPBCD) ; 3β,5α,6β-trihydroxy-cholan-24-oyl)glycine (TCG) ; Cyclodextrin ; Medicine (General) ; R5-920 ; Biology (General) ; QH301-705.5
    Subject code 610
    Language English
    Publishing date 2021-09-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Cross-species efficacy of enzyme replacement therapy for CLN1 disease in mice and sheep

    Hemanth R. Nelvagal / Samantha L. Eaton / Sophie H. Wang / Elizabeth M. Eultgen / Keigo Takahashi / Steven Q. Le / Rachel Nesbitt / Joshua T. Dearborn / Nicholas Siano / Ana C. Puhl / Patricia I. Dickson / Gerard Thompson / Fraser Murdoch / Paul M. Brennan / Mark Gray / Stephen N. Greenhalgh / Peter Tennant / Rachael Gregson / Eddie Clutton /
    James Nixon / Chris Proudfoot / Stefano Guido / Simon G. Lillico / C. Bruce A. Whitelaw / Jui-Yun Lu / Sandra L. Hofmann / Sean Ekins / Mark S. Sands / Thomas M. Wishart / Jonathan D. Cooper

    The Journal of Clinical Investigation, Vol 132, Iss

    2022  Volume 20

    Abstract: CLN1 disease, also called infantile neuronal ceroid lipofuscinosis (NCL) or infantile Batten disease, is a fatal neurodegenerative lysosomal storage disorder resulting from mutations in the CLN1 gene encoding the soluble lysosomal enzyme palmitoyl- ... ...

    Abstract CLN1 disease, also called infantile neuronal ceroid lipofuscinosis (NCL) or infantile Batten disease, is a fatal neurodegenerative lysosomal storage disorder resulting from mutations in the CLN1 gene encoding the soluble lysosomal enzyme palmitoyl-protein thioesterase 1 (PPT1). Therapies for CLN1 disease have proven challenging because of the aggressive disease course and the need to treat widespread areas of the brain and spinal cord. Indeed, gene therapy has proven less effective for CLN1 disease than for other similar lysosomal enzyme deficiencies. We therefore tested the efficacy of enzyme replacement therapy (ERT) by administering monthly infusions of recombinant human PPT1 (rhPPT1) to PPT1-deficient mice (Cln1–/–) and CLN1R151X sheep to assess how to potentially scale up for translation. In Cln1–/– mice, intracerebrovascular (i.c.v.) rhPPT1 delivery was the most effective route of administration, resulting in therapeutically relevant CNS levels of PPT1 activity. rhPPT1-treated mice had improved motor function, reduced disease-associated pathology, and diminished neuronal loss. In CLN1R151X sheep, i.c.v. infusions resulted in widespread rhPPT1 distribution and positive treatment effects measured by quantitative structural MRI and neuropathology. This study demonstrates the feasibility and therapeutic efficacy of i.c.v. rhPPT1 ERT. These findings represent a key step toward clinical testing of ERT in children with CLN1 disease and highlight the importance of a cross-species approach to developing a successful treatment strategy.
    Keywords Neuroscience ; Therapeutics ; Medicine ; R
    Language English
    Publishing date 2022-10-01T00:00:00Z
    Publisher American Society for Clinical Investigation
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Immune-Mediated Inflammation May Contribute to the Pathogenesis of Cardiovascular Disease in Mucopolysaccharidosis Type I.

    Omar Khalid / Moin U Vera / Philip L Gordts / N Matthew Ellinwood / Philip H Schwartz / Patricia I Dickson / Jeffrey D Esko / Raymond Y Wang

    PLoS ONE, Vol 11, Iss 3, p e

    2016  Volume 0150850

    Abstract: Background Cardiovascular disease, a progressive manifestation of α-L-iduronidase deficiency or mucopolysaccharidosis type I, continues in patients both untreated and treated with hematopoietic stem cell transplantation or intravenous enzyme replacement. ...

    Abstract Background Cardiovascular disease, a progressive manifestation of α-L-iduronidase deficiency or mucopolysaccharidosis type I, continues in patients both untreated and treated with hematopoietic stem cell transplantation or intravenous enzyme replacement. Few studies have examined the effects of α-L-iduronidase deficiency and subsequent glycosaminoglycan storage upon arterial gene expression to understand the pathogenesis of cardiovascular disease. Methods Gene expression in carotid artery, ascending, and descending aortas from four non-tolerized, non-enzyme treated 19 month-old mucopolysaccharidosis type I dogs was compared with expression in corresponding vascular segments from three normal, age-matched dogs. Data were analyzed using R and whole genome network correlation analysis, a bias-free method of categorizing expression level and significance into discrete modules. Genes were further categorized based on module-trait relationships. Expression of clusterin, a protein implicated in other etiologies of cardiovascular disease, was assessed in canine and murine mucopolysaccharidosis type I aortas via Western blot and in situ immunohistochemistry. Results Gene families with more than two-fold, significant increased expression involved lysosomal function, proteasome function, and immune regulation. Significantly downregulated genes were related to cellular adhesion, cytoskeletal elements, and calcium regulation. Clusterin gene overexpression (9-fold) and protein overexpression (1.3 to 1.62-fold) was confirmed and located specifically in arterial plaques of mucopolysaccharidosis-affected dogs and mice. Conclusions Overexpression of lysosomal and proteasomal-related genes are expected responses to cellular stress induced by lysosomal storage in mucopolysaccharidosis type I. Upregulation of immunity-related genes implicates the potential involvement of glycosaminoglycan-induced inflammation in the pathogenesis of mucopolysaccharidosis-related arterial disease, for which clusterin represents a potential biomarker.
    Keywords Medicine ; R ; Science ; Q
    Subject code 570
    Language English
    Publishing date 2016-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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