scholarly journals Clickable Galactose Analogs for Imaging Glycans in Developing Zebrafish

2019 ◽  
Author(s):  
Jessica Daughtry ◽  
Wendy Cao ◽  
Johnny Ye ◽  
Jeremy Baskin
Keyword(s):  
Metabolic Flux ◽  
Lysosomal Storage Diseases ◽  
Underlying Disease ◽  
Uridine Diphosphate ◽  
Lysosomal Storage ◽  
Galactose Metabolism ◽  
New Class ◽  
Complex Glycans ◽  
Universal Donor

<p>Galactose is one of only nine monosaccharide precursors used to build complex glycans in vertebrates. Defects in galactose metabolism cause galactosemia and lysosomal storage diseases, and the ability to visualize metabolic flux through these pathways would help to understand mechanisms underlying disease pathogenesis. Bioorthogonal metabolic reporters are widely used tools to image glycan biosynthesis, but to date, no galactose analogs have capitalized on this strategy. We demonstrate that the galactose salvage pathway is remarkably intolerant of unnatural galactose and galactose-1-phosphate analogs. Subtle modifications to uridine diphosphate galactose (UDP-Gal), the universal donor for galactosyltransferases, however, yielded effective metabolic probes for labeling glycans in vivo. We applied 6-alkynyl UDP-Gal, followed by click chemistry tagging, to visualize glycosylation during zebrafish development, revealing a striking accumulation into glycan-rich ridges within the organism’s enveloping layer. UDP-Gal analogs represent a new class of glycan metabolic probes for revealing physiological and pathological changes in glycosylation in vivo.</p>

scholarly journals Clickable Galactose Analogs for Imaging Glycans in Developing Zebrafish

2019 ◽  
Author(s):  
Jessica Daughtry ◽  
Wendy Cao ◽  
Johnny Ye ◽  
Jeremy Baskin
Keyword(s):  
Metabolic Flux ◽  
Lysosomal Storage Diseases ◽  
Underlying Disease ◽  
Uridine Diphosphate ◽  
Lysosomal Storage ◽  
Galactose Metabolism ◽  
New Class ◽  
Complex Glycans ◽  
Universal Donor

<p>Galactose is one of only nine monosaccharide precursors used to build complex glycans in vertebrates. Defects in galactose metabolism cause galactosemia and lysosomal storage diseases, and the ability to visualize metabolic flux through these pathways would help to understand mechanisms underlying disease pathogenesis. Bioorthogonal metabolic reporters are widely used tools to image glycan biosynthesis, but to date, no galactose analogs have capitalized on this strategy. We demonstrate that the galactose salvage pathway is remarkably intolerant of unnatural galactose and galactose-1-phosphate analogs. Subtle modifications to uridine diphosphate galactose (UDP-Gal), the universal donor for galactosyltransferases, however, yielded effective metabolic probes for labeling glycans in vivo. We applied 6-alkynyl UDP-Gal, followed by click chemistry tagging, to visualize glycosylation during zebrafish development, revealing a striking accumulation into glycan-rich ridges within the organism’s enveloping layer. UDP-Gal analogs represent a new class of glycan metabolic probes for revealing physiological and pathological changes in glycosylation in vivo.</p>

scholarly journals Pharmacological Chaperones for the Mucopolysaccharidoses

2019 ◽  
Author(s):  
Juan Camilo Losada Diaz ◽  
Jacobo Cepeda Del Castillo ◽  
Edwin Alexander Rodríguez López ◽  
Carlos Javier Alméciga-Díaz
Keyword(s):  
Lysosomal Storage Diseases ◽  
Lysosomal Storage ◽  
In Vivo Evaluation ◽  
Pharmacological Chaperones ◽  
Cellular Models ◽  
Mps Ii ◽  
Enzyme Substrates ◽  
Lower Production

The mucopolysaccharidoses (MPS) are a group of 11 lysosomal storage diseases (LSDs) produced by mutations in the enzymes involved in the lysosomal catabolism of glycosaminoglycans. Most of the mutations affecting these enzymes may lead to changes in processing, folding, glycosylation, pH stability, protein aggregation, and defective transport to the lysosomes. The use of small molecules, called pharmacological chaperones (PCs), that can restore the folding, trafficking and biological activity of mutated enzymes has been extensively explored in LSDs as a therapeutic alternative. PCs have the advantage of wide tissue distribution, potential oral administration, lower production cost, and fewer issues of immunogenicity. In this paper, we will review the advances in the identification and characterization of PCs for the MPS. These molecules, mainly based in molecules mimicking the enzyme substrates, have been described for MPS II, IVA, and IVB, showing a mutation-dependent enhancement of the mutated enzymes. Although the results show the potential of this strategy, further studies should focus in the development of disease-specific cellular models that allow a proper screening and evaluation of the identified PCs. In addition, in vivo evaluation, both pre-clinical and clinical, should be performed, before they can become a real therapeutic strategy for the treatment of MPS patients.

scholarly journals Advances in the Development of Pharmacological Chaperones for the Mucopolysaccharidoses

2019 ◽  
Vol 21 (1) ◽  
pp. 232 ◽  
Author(s):  
Juan Camilo Losada Díaz ◽  
Jacobo Cepeda del Castillo ◽  
Edwin Alexander Rodriguez-López ◽  
Carlos J. Alméciga-Díaz
Keyword(s):  
Lysosomal Storage Diseases ◽  
Lysosomal Storage ◽  
In Vivo Evaluation ◽  
Pharmacological Chaperones ◽  
Enzyme Replacement ◽  
Cellular Models ◽  
Mps Ii ◽  
Lower Production

The mucopolysaccharidoses (MPS) are a group of 11 lysosomal storage diseases (LSDs) produced by mutations in the enzymes involved in the lysosomal catabolism of glycosaminoglycans. Most of the mutations affecting these enzymes may lead to changes in processing, folding, glycosylation, pH stability, protein aggregation, and defective transport to the lysosomes. It this sense, it has been proposed that the use of small molecules, called pharmacological chaperones (PCs), can restore the folding, trafficking, and biological activity of mutated enzymes. PCs have the advantages of wide tissue distribution, potential oral administration, lower production cost, and fewer issues of immunogenicity than enzyme replacement therapy. In this paper, we will review the advances in the identification and characterization of PCs for the MPS. These molecules have been described for MPS II, IVA, and IVB, showing a mutation-dependent enhancement of the mutated enzymes. Although the results show the potential of this strategy, further studies should focus in the development of disease-specific cellular models that allow a proper screening and evaluation of PCs. In addition, in vivo evaluation, both pre-clinical and clinical, should be performed, before they can become a real therapeutic strategy for the treatment of MPS patients.

scholarly journals Gene therapy: prospects for glycolipid storage diseases

2003 ◽  
Vol 358 (1433) ◽  
pp. 921-925 ◽  
Author(s):  
Volkmar Gieselmann ◽  
Ulrich Matzner ◽  
Diana Klein ◽  
Jan Eric Mansson ◽  
Rudi D'Hooge ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Mouse Models ◽  
Metachromatic Leukodystrophy ◽  
Lysosomal Storage Diseases ◽  
Degradation Pathway ◽  
Lysosomal Storage ◽  
Storage Diseases ◽  
Lysosomal Disorders ◽  
Lysosomal Diseases

Lysosomal storage diseases comprise a group of about 40 disorders, which in most cases are due to the deficiency of a lysosomal enzyme. Since lysosomal enzymes are involved in the degradation of various compounds, the diseases can be further subdivided according to which pathway is affected. Thus, enzyme deficiencies in the degradation pathway of glycosaminoglycans cause mucopolysaccharidosis, and deficiencies affecting glycopeptides cause glycoproteinosis. In glycolipid storage diseases enzymes are deficient that are involved in the degradation of sphingolipids. Mouse models are available for most of these diseases, and some of these mouse models have been used to study the applicability of in vivo gene therapy. We review the rationale for gene therapy in lysosomal disorders and present data, in particular, about trials in an animal model of metachromatic leukodystrophy. The data of these trials are compared with those obtained with animal models of other lysosomal diseases.

scholarly journals Exploiting toxin internalization receptors to enhance delivery of proteins to lysosomes for enzyme replacement therapy

2020 ◽  
Author(s):  
Seiji N. Sugiman-Marangos ◽  
Greg L. Beilhartz ◽  
Xiaochu Zhao ◽  
Dongxia Zhou ◽  
Rong Hua ◽  
...  
Keyword(s):  
Enzyme Replacement Therapy ◽  
Replacement Therapy ◽  
Diphtheria Toxin ◽  
Lysosomal Storage Diseases ◽  
Target Cells ◽  
Lysosomal Storage ◽  
Recombinant Enzymes ◽  
Storage Diseases ◽  
Enzyme Replacement

AbstractLysosomal storage diseases are a group of over 70 inherited genetic diseases caused by a defect or deficiency in a lysosomal protein. Enzyme replacement therapy, in which a functional copy of the defective enzyme is injected either systemically or directly into the brain of affected individuals, has proven to be an effective strategy for treating certain lysosomal storage diseases; however, the inefficient uptake of recombinant enzymes into cells and tissues via the low-affinity mannose-6-phosphate receptor prohibits broader utility of replacement therapy. Here, to improve the efficiency and efficacy of lysosomal enzyme uptake, we exploited the strategy used by diphtheria toxin to enter into the endo-lysosomal network of cells by creating a chimera between the receptor-binding fragment of diphtheria toxin and the lysosomal hydrolase TPP1. We show that the targeted TPP1 chimera binds with high affinity to target cells and is delivered into lysosomes with much greater efficiency than TPP1 alone. Further, we demonstrate efficient and durable uptake of the chimera in vivo following intracerebroventricular injection in mice lacking TPP1. Targeting the highly efficient diphtheria toxin internalization pathway represents a novel approach for improving the efficacy and utility of enzyme replacement therapy for treating lysosomal storage diseases.

scholarly journals Progressive pulmonary hypertension in a patient with type 1 Gaucher disease

2017 ◽  
Vol 89 (10) ◽  
pp. 71-74
Author(s):  
R V Ponomarev ◽  
S V Model ◽  
O M Averbukh ◽  
A M Gavrilov ◽  
G M Galstyan ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Gaucher Disease ◽  
Bone Lesion ◽  
Clinical Manifestations ◽  
Lysosomal Storage Diseases ◽  
Underlying Disease ◽  
Lysosomal Storage ◽  
Macrophage Dysfunction ◽  
Type 1 Gaucher Disease

Gaucher disease is the most common form of hereditary enzymopathies combined into a group of lysosomal storage diseases. The basis for the disease is a hereditary deficiency of the activity of acid β-glucosidase, a lysosomal enzyme involved in the catabolism of lipids, which results in the accumulation of nonutilized cellular metabolism products in the macrophage lysosomes. The main clinical manifestations of type 1 Gaucher disease are cytopenia, hepatomegaly, and splenomegaly, and bone lesion. One of the atypical clinical manifestations of Gaucher disease is damage to the lungs with the development of pulmonary hypertension, which is usually considered within the underlying disease — the development of pneumosclerosis due to macrophage dysfunction. The paper describes a case of progressive pulmonary hypertension in a patient with type 1 Gaucher disease.

Cord Blood Transplantation for Lysosomal Storage Diseases Demonstrates the Potential of Cord Blood Cells for Future Cellular Therapies.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3602-3602 ◽  
Author(s):  
Joanne Kurtzberg ◽  
William Krivit
Keyword(s):  
Cord Blood ◽  
Blood Cells ◽  
Lysosomal Storage Diseases ◽  
Krabbe Disease ◽  
Unrelated Donor ◽  
Lysosomal Storage ◽  
Cellular Therapies ◽  
Myeloablative Chemotherapy ◽  
Cord Blood Cells

Cord blood stem and progenitor cells can rescue the bone marrow and immune system of pediatric and selected adult patients undergoing myeloablative chemotherapy. Cord blood cells exhibit immunologic tolerance allowing transplantation across partially mismatched HLA barriers increasing access to allogeneic transplantation therapy for patient searching for unrelated donors. Cord blood cells may also be capable of transdifferentiation into non-hematopoietic tissues. This property would render this stem and progenitor cell source an ideal candidate for cellular therapies targeting tissue repair and regeneration. Since 1995, >100 infants and children with inborn errors of metabolism have been transplanted with cord blood. The results in these pediatric patients serve as a demonstration that cord blood cells can differentiate into non-hematopoietic tissues. All children wer! e prepared for transplant with myeloablative chemotherapy consisting of busulfan, cyclosphosphamide and antithymocyte globulin. Prophylaxis against GvHD was adminstered with cyclosporine and methylprednisolone. Supportive care was provided with IVIG, G-CSF, low dose heparin for VOD prophylaxis, leukocyte depleted and irradiated PRBC and platelet transfusions, total parenteral nutrition, prophylactic antiviral and antifungal antibiotics and empiric antibiotic therapy for fever. Thirty five young children with Hurler Syndrome (MPS I) were transplanted with partially HLA mismatched unrelated donor umbiloical cord blood over the past 8 years. All had the severe genotype and phenotype. Neutrophil(ANC 500/uL) and platelet (>50k/uL) engraftment occurred in a median of 20 and 63 days respectively. Moderate to severe acute GvHD occurred in 28% of patients. Extensive chronic GvHD was not seen. Eighty-seven percent of patients are surviving event-free for a median >3 years. All surviving children remain full donor chimeras and have shown increasing velocities of gains of neurocognitive functions. Skeletal growth improved with only 4/11 children with severe kyphosis requiring orthopedic surgery post transplantation therapy. No child developed clinical cardiac disease and corneal clouding improved in all. Additional children (n=60)with lysosomal storage diseases including metachromatic leukodystrophy, adrenoleukodystrophy and globoid leukodystrophy (Krabbe Disease), MPS III (Sanfilippo Syndrome) and GM2 (Tay Sachs Disease) have been transplanted with unrelated donor umbilical cord blood over the past 9 years. In asymptomatic children, disease was arrested before the onset of neurologic dysfunction. In symptomatic children disease progression was arrested within 6–9 months of the transplant procedure. In a child with advanced krabbe disease who died 1 year post transplant, engraftment of donor cells was noted in the brain. Differentiation to oligodendrocytes was demonstrated in vivo and subsequently, in vivo. In a child with MPS III (Sanfillipo syndrome), donor cells differentiated into cardiac myocytes in the heart 6 months post transplant.These studies suggest that cord blood is capable of transdifferentiation into non-hematopoietic lineages. While additional studies are needed to fully define the potential of these cells for cellular therapies and tissue repair, we believe that UCB is a unique stem cell source that will be an important resource for cellular therapies in the future.

Electron Microscopy in the diagnosis of lysosomal storage diseases

1989 ◽  
Vol 47 ◽  
pp. 866-867
Author(s):  
Carole Vogler ◽  
Harvey S. Rosenberg
Keyword(s):  
Electron Microscopy ◽  
Lysosomal Enzyme ◽  
Rectal Mucosa ◽  
Lysosomal Storage Diseases ◽  
Cell Types ◽  
Lysosomal Storage ◽  
Storage Material ◽  
Ultrastructural Examination ◽  
Blood Leukocytes ◽  
Storage Diseases

Diagnostic procedures for evaluation of patients with lysosomal storage diseases (LSD) seek to identify a deficiency of a responsible lysosomal enzyme or accumulation of a substance that requires the missing enzyme for degradation. Most patients with LSD have progressive neurological degeneration and may have a variety of musculoskeletal and visceral abnormalities. In the LSD, the abnormally diminished lysosomal enzyme results in accumulation of unmetabolized catabolites in distended lysosomes. Because of the subcellular morphology and size of lysosomes, electron microscopy is an ideal tool to study tissue from patients with suspected LSD. In patients with LSD all cells lack the specific lysosomal enzyme but the distribution of storage material is dependent on the extent of catabolism of the substrate in each cell type under normal circumstances. Lysosmal storages diseases affect many cell types and tissues. Storage material though does not accumulate in all tissues and cell types and may be different biochemically and morphologically in different tissues.Conjunctiva, skin, rectal mucosa and peripheral blood leukocytes may show ultrastructural evidence of lysosomal storage even in the absence of clinical findings and thus any of these tissues can be used for ultrastructural examination in the diagnostic evaluation of patients with suspected LSD. Biopsy of skin and conjunctiva are easily obtained and provide multiple cell types including endothelium, epithelium, fibroblasts and nerves for ultrastructural study. Fibroblasts from skin and conjunctiva can also be utilized for the initiation of tissue cultures for chemical assays. Brain biopsy has been largely replaced by biopsy of more readily obtained tissue and by biochemical assays. Such assays though may give equivical or nondiagnostic results and in some lysosomal storage diseases an enzyme defect has not yet been identified and diagnoses can be made only by ultrastructural examination.

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