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3. Clinical outcomes and sustained biochemical engraftment following ex-vivo autologous stem cell gene therapy for mucopolysaccharidosis type IIIA

Author

Jones, Simon, primary, Kinsella, Jane, additional, Holley, Rebecca J., additional, Potter, Jane, additional, Booth, Claire, additional, Buckland, Karen, additional, Rust, Stewart, additional, Bromley, Rebecca, additional, Church, Heather J., additional, Lee, Helena, additional, Ford, Laura, additional, Learmonth, Yuko Ishikawa, additional, Searle, Rachel, additional, Ellison, Stuart M., additional, Wynn, Robert, additional, and Bigger, Brian, additional

Published
2024
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7. Neuropathology in mouse models of mucopolysaccharidosis type I, IIIA and IIIB.

Author

Wilkinson, Fiona L, Holley, Rebecca J, Langford-Smith, Kia J, Badrinath, Soumya, Liao, Aiyin, Langford-Smith, Alex, Cooper, Jonathan D, Jones, Simon A, Wraith, J Ed, Wynn, Rob F, Merry, Catherine LR, and Bigger, Brian W

Subjects
Parietal Lobe, Somatosensory Cortex, Neurons, Lysosomes, Animals, Mice, Mucopolysaccharidosis I, Mucopolysaccharidosis III, Disease Models, Animal, Disease Progression, G(M2) Ganglioside, Glycosaminoglycans, Heparitin Sulfate, Carrier Proteins, Cytokines, Immunohistochemistry, Female, Male, Vesicle-Associated Membrane Protein 2, Homer Scaffolding Proteins, Disease Models, Animal, General Science & Technology
Abstract

Mucopolysaccharide diseases (MPS) are caused by deficiency of glycosaminoglycan (GAG) degrading enzymes, leading to GAG accumulation. Neurodegenerative MPS diseases exhibit cognitive decline, behavioural problems and shortened lifespan. We have characterised neuropathological changes in mouse models of MPSI, IIIA and IIIB to provide a better understanding of these events.Wild-type (WT), MPSI, IIIA and IIIB mouse brains were analysed at 4 and 9 months of age. Quantitative immunohistochemistry showed significantly increased lysosomal compartment, GM2 ganglioside storage, neuroinflammation, decreased and mislocalised synaptic vesicle associated membrane protein, (VAMP2), and decreased post-synaptic protein, Homer-1, in layers II/III-VI of the primary motor, somatosensory and parietal cortex. Total heparan sulphate (HS), was significantly elevated, and abnormally N-, 6-O and 2-O sulphated compared to WT, potentially altering HS-dependent cellular functions. Neuroinflammation was confirmed by significantly increased MCP-1, MIP-1α, IL-1α, using cytometric bead arrays. An overall genotype effect was seen in all parameters tested except for synaptophysin staining, neuronal cell number and cortical thickness which were not significantly different from WT. MPSIIIA and IIIB showed significantly more pronounced pathology than MPSI in lysosomal storage, astrocytosis, microgliosis and the percentage of 2-O sulphation of HS. We also observed significant time progression of all genotypes from 4-9 months in lysosomal storage, astrocytosis, microgliosis and synaptic disorganisation but not GM2 gangliosidosis. Individual genotype*time differences were disparate, with significant progression from 4 to 9 months only seen for MPSIIIB with lysosomal storage, MPSI with astrocytocis and MPSIIIA with microgliosis as well as neuronal loss. Transmission electron microscopy of MPS brains revealed dystrophic axons, axonal storage, and extensive lipid and lysosomal storage. These data lend novel insight to MPS neuropathology, suggesting that MPSIIIA and IIIB have more pronounced neuropathology than MPSI, yet all are still progressive, at least in some aspects of neuropathology, from 4-9 months.

Published
2012

8. Biochemical Engraftment and Clinical Outcomes Following Ex-Vivo Autologous Stem Cell Gene Therapy for Mucopolysaccharidosis Type IIIA

Author

Wynn, Robert F, primary, Kinsella, Jane L, additional, Holley, Rebecca J, additional, Potter, Jane, additional, Thrasher, Adrian J., additional, Booth, Claire, additional, Buckland, Karen, additional, Izotova, Natalia, additional, Rust, Stewart, additional, Weisberg, Daniel, additional, Church, Heather J, additional, Tylee, Karen L, additional, Brammeier, Kathryn L, additional, Lee, Helena, additional, Ford, Laura, additional, Sadegholnejat, Atusa, additional, Jones, Simon A, additional, Ellison, Stuart, additional, and Bigger, Brian, additional

Published
2022
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10. Clinical trial update: Ex-vivo autologous hematopoietic stem cell gene therapy in MPS IIIA

Author

Jones, Simon A., primary, Kinsella, Jane L., additional, Potter, Jane, additional, Thrasher, Adrian, additional, Booth, Claire, additional, Buckland, Karen, additional, Izotova, Natalia, additional, Rust, Stewart, additional, Weisberg, Daniel, additional, Church, Heather, additional, Tylee, Karen, additional, Lee, Helena, additional, Ford, Laura, additional, Holley, Rebecca J., additional, Ellison, Stuart, additional, Bigger, Brian W., additional, and Wynn, Robert F., additional

Published
2022
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12. Contributor contact details

Author

Bosworth, Lucy A., primary, Downes, Sandra, additional, Wang, Linge, additional, Ryan, Anthony J., additional, Christian, Paul, additional, Robb, Brendan, additional, Lennox, Barry, additional, Wilson, Alison, additional, Bassi, Anita, additional, Gough, Julie, additional, Zakikhani, Mohsen, additional, Hardingham, Tim, additional, McKeon-Fischer, Kristin D., additional, Freeman, Joseph W., additional, Bosworth, Lucy A., additional, Wang, Ms Charlene, additional, Koh, Ms Huishan, additional, Ramakrishna, Seeram, additional, Liao, Susan, additional, Marc Simonet, Ir, additional, Driessen-Mol, Anita, additional, Bouten, Carlijn V.C., additional, Baaijens, Frank P.T., additional, Baker, Simon C., additional, Southgate, Jennifer, additional, Acocella, Fabio, additional, Brizzola, Stefano, additional, Rehman, Ihtesham Ur, additional, Khan, Abdul Samad, additional, Subramanian, Anuradha, additional, Krishnan, Uma Maheswari, additional, Sethuraman, Swaminathan, additional, Hayes, Thomas R., additional, Su, Bo, additional, Schuler, Stephanie, additional, Lennon, Rachel, additional, Wan, Jimmy D.D., additional, Dunne, Mark, additional, Cosgrove, Karen, additional, Meade, Kate, additional, Holley, Rebecca J., additional, and Merry, Catherine L.R., additional

Published
2011
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13. Haematopoietic stem cell gene therapy with IL ‐1Ra rescues cognitive loss in mucopolysaccharidosis IIIA

Author

Parker, Helen, primary, Ellison, Stuart M, additional, Holley, Rebecca J, additional, O'Leary, Claire, additional, Liao, Aiyin, additional, Asadi, Jalal, additional, Glover, Emily, additional, Ghosh, Arunabha, additional, Jones, Simon, additional, Wilkinson, Fiona L, additional, Brough, David, additional, Pinteaux, Emmanuel, additional, Boutin, Hervé, additional, and Bigger, Brian W, additional

Published
2020
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14. An Improved Adeno-Associated Virus Vector for Neurological Correction of the Mouse Model of Mucopolysaccharidosis IIIA

Author

Gray, Anna L., primary, O'Leary, Claire, additional, Liao, Aiyin, additional, Agúndez, Leticia, additional, Youshani, Amir S., additional, Gleitz, Hélène F., additional, Parker, Helen, additional, Taylor, Jessica T., additional, Danos, Olivier, additional, Hocquemiller, Michaël, additional, Palomar, Nuria, additional, Linden, R. Michael, additional, Henckaerts, Els, additional, Holley, Rebecca J., additional, and Bigger, Brian W., additional

Published
2019
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15. Comparative Quantification of the Surfaceome of Human Multipotent Mesenchymal Progenitor Cells

Author

Holley, Rebecca J., Tai, Guangping, Williamson, Andrew J.K., Taylor, Samuel, Cain, Stuart A., Richardson, Stephen M., Merry, Catherine L.R., Whetton, Anthony D., Kielty, Cay M., and Canfield, Ann E.

Subjects
lcsh:R5-920, lcsh:Biology (General), lcsh:Medicine (General), lcsh:QH301-705.5
Abstract

SummaryMesenchymal progenitor cells have great therapeutic potential, yet incomplete characterization of their cell-surface interface limits their clinical exploitation. We have employed subcellular fractionation with quantitative discovery proteomics to define the cell-surface interface proteome of human bone marrow mesenchymal stromal/stem cells (MSCs) and human umbilical cord perivascular cells (HUCPVCs). We compared cell-surface-enriched fractions from MSCs and HUCPVCs (three donors each) with adult mesenchymal fibroblasts using eight-channel isobaric-tagging mass spectrometry, yielding relative quantification on >6,000 proteins with high confidence. This approach identified 186 upregulated mesenchymal progenitor biomarkers. Validation of 10 of these markers, including ROR2, EPHA2, and PLXNA2, confirmed upregulated expression in mesenchymal progenitor populations and distinct roles in progenitor cell proliferation, migration, and differentiation. Our approach has delivered a cell-surface proteome repository that now enables improved selection and characterization of human mesenchymal progenitor populations.

Published
2015

18. A novel adeno-associated virus capsid with enhanced neurotropism corrects a lysosomal transmembrane enzyme deficiency

Author

Tordo, Julie, primary, O’Leary, Claire, additional, Antunes, André S L M, additional, Palomar, Nuria, additional, Aldrin-Kirk, Patrick, additional, Basche, Mark, additional, Bennett, Antonette, additional, D’Souza, Zelpha, additional, Gleitz, Hélène, additional, Godwin, Annie, additional, Holley, Rebecca J, additional, Parker, Helen, additional, Liao, Ai Yin, additional, Rouse, Paul, additional, Youshani, Amir Saam, additional, Dridi, Larbi, additional, Martins, Carla, additional, Levade, Thierry, additional, Stacey, Kevin B, additional, Davis, Daniel M, additional, Dyer, Adam, additional, Clément, Nathalie, additional, Björklund, Tomas, additional, Ali, Robin R, additional, Agbandje-McKenna, Mavis, additional, Rahim, Ahad A, additional, Pshezhetsky, Alexey, additional, Waddington, Simon N, additional, Linden, R Michael, additional, Bigger, Brian W, additional, and Henckaerts, Els, additional

Published
2018
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19. Macrophage enzyme and reduced inflammation drive brain correction of mucopolysaccharidosis IIIB by stem cell gene therapy

Author

Holley, Rebecca J, primary, Ellison, Stuart M, additional, Fil, Daniel, additional, O’Leary, Claire, additional, McDermott, John, additional, Senthivel, Nishanthi, additional, Langford-Smith, Alexander W W, additional, Wilkinson, Fiona L, additional, D’Souza, Zelpha, additional, Parker, Helen, additional, Liao, Aiyin, additional, Rowlston, Samuel, additional, Gleitz, Hélène F E, additional, Kan, Shih-Hsin, additional, Dickson, Patricia I, additional, and Bigger, Brian W, additional

Published
2017
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28. Hematopoietic Stem Cell and Gene Therapy Corrects Primary Neuropathology and Behavior in Mucopolysaccharidosis IIIA Mice

Author

Langford-Smith, Alexander, primary, Wilkinson, Fiona L, additional, Langford-Smith, Kia J, additional, Holley, Rebecca J, additional, Sergijenko, Ana, additional, Howe, Steven J, additional, Bennett, William R, additional, Jones, Simon A, additional, Wraith, JE, additional, Merry, Catherine LR, additional, Wynn, Robert F, additional, and Bigger, Brian W, additional

Published
2012
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29. Excess Heparan Sulphate Inhibits CXCL12-Mediated Hematopoietic Cell Migration and Engraftment After Bone Marrow Transplant in Mice with Mucopolysaccharidosis Type I,

Author

Watson, H. Angharad, primary, Holley, Rebecca J, additional, Langford-Smith, Kia J, additional, Wilkinson, Fiona L, additional, van Kuppevelt, Toin H, additional, Wynn, Robert, additional, Wraith, J. Ed, additional, Merry, Catherine L R, additional, and Bigger, Brian W, additional

Published
2011
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30. Mucopolysaccharidosis Type I, Unique Structure of Accumulated Heparan Sulfate and Increased N-Sulfotransferase Activity in Mice Lacking α-l-iduronidase

Author

Holley, Rebecca J., primary, Deligny, Audrey, additional, Wei, Wei, additional, Watson, H. Angharad, additional, Niñonuevo, Milady R., additional, Dagälv, Anders, additional, Leary, Julie A., additional, Bigger, Brian W., additional, Kjellén, Lena, additional, and Merry, Catherine L.R., additional

Published
2011
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35. Immobilization of heparan sulfate on electrospun meshes to support embryonic stem cell culture and differentiation

Author

Kathryn J. White, Andrew Marson, Rebecca J. Holley, Donna Tillotson, Kate Meade, Catherine L.R. Merry, Claire E. Pickford, Jason D. Whittle, Toin H. van Kuppevelt, Anthony J. Day, Meade, Kate A, White, Kathryn J, Pickford, Claire E, Holley, Rebecca J, Marson, Andrew, Tillotson, Donna, Van Kuppevelt, Toin H, Whittle, Jason D, Day, Anthony J, and Merry, Catherine LR

Subjects
Scaffold, Polymers, Cellular differentiation, Cell Culture Techniques, Glycobiology, Oligosaccharides, Glycobiology and Extracellular Matrices, Biocompatible Materials, Neurodifferentiation, 02 engineering and technology, Disaccharides, Regenerative Medicine, Biochemistry, Regenerative medicine, Oligosaccharide, chemistry.chemical_compound, Epitopes, Mice, Induced pluripotent stem cell, Cells, Cultured, Glycosaminoglycans, 0303 health sciences, extracellular matrices, Chemistry, Cell Differentiation, Heparan sulfate, embryonic stem cells, 021001 nanoscience & nanotechnology, electrospuns, 3. Good health, Cell biology, Intercellular Signaling Peptides and Proteins, Stem cell, 0210 nano-technology, regenerative medicine, Mice, Transgenic, Allylamine, Biomaterials, 03 medical and health sciences, Peptide Library, Embryonic Stem Cell, Growth Factors, Animals, Regeneration, Molecular Biology, Embryonic Stem Cells, 030304 developmental biology, Regeneration (biology), Cell Biology, Tissue engineering and pathology [NCMLS 3], Embryonic stem cell, future applications, Glycosaminoglycan, allyl amine, glycosaminoglycans, heparan sulfates, Heparitin Sulfate, Plasma Polymerization
Abstract

Background: Glycosaminoglycans influence stem cell fate but their combination with biomaterials remains to be optimized. Results: GAG bound to scaffolds presented essential sulfation epitopes and proved biologically active. Conclusion: Use of plasma polymerized allylamine proved effective in functionalizing a fibrous extracellular matrix mimic. Significance: The biomaterial has broad applicability to stem cell culture and has potential future applications in regenerative medicine., As our understanding of what guides the behavior of multi- and pluripotent stem cells deepens, so too does our ability to utilize certain cues to manipulate their behavior and maximize their therapeutic potential. Engineered, biologically functionalized materials have the capacity to influence stem cell behavior through a powerful combination of biological, mechanical, and topographical cues. Here, we present the development of a novel electrospun scaffold, functionalized with glycosaminoglycans (GAGs) ionically immobilized onto the fiber surface. Bound GAGs retained the ability to interact with GAG-binding molecules and, crucially, presented GAG sulfation motifs fundamental to mediating stem cell behavior. Bound GAG proved to be biologically active, rescuing the neural differentiation capacity of heparan sulfate-deficient mouse embryonic stem cells and functioning in concert with FGF4 to facilitate the formation of extensive neural processes across the scaffold surface. The combination of GAGs with electrospun scaffolds creates a biomaterial with potent applicability for the propagation and effective differentiation of pluripotent stem cells.

Published
2013

36. Use of flow cytometry for characterization and fractionation of cell populations based on their expression of heparan sulfate epitopes.

Author

Holley RJ, Smith RA, van de Westerlo EM, Pickford CE, Merry CL, and van Kuppevelt TH

Subjects
Animals, Antibody Specificity, Cell Separation, Mice, Staining and Labeling, Cell Fractionation methods, Epitopes immunology, Flow Cytometry methods, Heparitin Sulfate immunology
Abstract

The ability to characterize alterations in heparan sulfate (HS) structure during development or as a result of loss or mutation of one or more components of the HS biosynthetic pathway is essential for broad understanding of the effects these changes may have on cell/tissue function. The use of anti-HS antibodies provides an opportunity to study HS chain composition in situ, with a multitude of different antibodies having been generated that recognize subtle differences in HS patterning, with the number and positioning of sulfate groups influencing antibody binding affinity. Flow cytometry is a valuable technique to enable the rapid characterization of the changes in HS-specific antibody binding in situ, allowing multiple cell types to be directly compared. Additionally fluorescent-activated cell sorting (FACS) allows fractionation of cells based on their HS-epitope expression.

Published
2015
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