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101. Insulin-like Growth Factor 2 Overexpression Induces β-Cell Dysfunction and Increases Beta-cell Susceptibility to Damage

Author

Casellas, Alba, primary, Mallol, Cristina, additional, Salavert, Ariana, additional, Jimenez, Veronica, additional, Garcia, Miquel, additional, Agudo, Judith, additional, Obach, Mercè, additional, Haurigot, Virginia, additional, Vilà, Laia, additional, Molas, Maria, additional, Lage, Ricardo, additional, Morró, Meritxell, additional, Casana, Estefania, additional, Ruberte, Jesús, additional, and Bosch, Fatima, additional

Published
2015
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103. Characterization of a Recombinant Adeno-Associated Virus Type 2 Reference Standard Material

Author

Darmon, Christophe, Chtarto, Abdelwahed, Doria, Monica, Conlon, Thomas, Philipsberg, Tina, Beecham, E. Jeffrey, Clark, K. Reed, Leuchs, Barbara, Douar, Anne, Korn, Michael T., Chiorini, John A., Leon, Xavier, Bose, Mahuya, Giacca, Mauro, Francis, Joyce D., Lock, Martin, Korytov, Irina, Müller, Marcus, Blouin-Tavel, Véronique, Moullier, Philippe, Auricchio, Alberto, Ozawa, Keiya, Melas, Catherine, Lux, Gabriele, Byrne, Barry J., McGorray, Susan, Bosch, Fatima, Flotte, Terence R., Francois, Achille, Caton, Tina, Ayuso, Eduard, and Mizukami, Hiroaki

Abstract

A recombinant adeno-associated virus serotype 2 Reference Standard Material (rAAV2 RSM) has been produced and characterized with the purpose of providing a reference standard for particle titer, vector genome titer, and infectious titer for AAV2 gene transfer vectors. Production and purification of the reference material were carried out by helper virus–free transient transfection and chromatographic purification. The purified bulk material was vialed, confirmed negative for microbial contamination, and then distributed for characterization along with standard assay protocols and assay reagents to 16 laboratories worldwide. Using statistical transformation and modeling of the raw data, mean titers and confidence intervals were determined for capsid particles ({X}, 9.18 × 1011 particles/ml; 95% confidence interval [CI], 7.89 × 1011 to 1.05 × 1012 particles/ml), vector genomes ({X}, 3.28 × 1010 vector genomes/ml; 95% CI, 2.70 × 1010 to 4.75 × 1010 vector genomes/ml), transducing units ({X}, 5.09 × 108 transducing units/ml; 95% CI, 2.00 × 108 to 9.60 × 108 transducing units/ml), and infectious units ({X}, 4.37 × 109 TCID50 IU/ml; 95% CI, 2.06 × 109 to 9.26 × 109 TCID50 IU/ml). Further analysis confirmed the identity of the reference material as AAV2 and the purity relative to nonvector proteins as greater than 94%. One obvious trend in the quantitative data was the degree of variation between institutions for each assay despite the relatively tight correlation of assay results within an institution. This relatively poor degree of interlaboratory precision and accuracy was apparent even though attempts were made to standardize the assays by providing detailed protocols and common reagents. This is the first time that such variation between laboratories has been thoroughly documented and the findings emphasize the need in the field for universal reference standards. The rAAV2 RSM has been deposited with the American Type Culture Collection and is available to the scientific community to calibrate laboratory-specific internal titer standards. Anticipated uses of the rAAV2 RSM are discussed.

Published
2010
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104. Manufacturing and characterization of a recombinant adeno-associated virus type 8 reference standard material

Author

Ayuso, Eduard, Leon, Xavier, Bosch, Fatima, Blouin, Veronique, Darmon, Christophe, Moullier, Philippe, Lock, Martin, Alvira, Mauricio M.R., McGorray, Susan, Auricchio, Alberto, Doria, Monica, Bucher, Stephanie, Chtarto, Abdelwahed, Melas, Catherine, Bockstael, Olivier, Clark, Reed K.R., Fountain, Will, Gao, Guangping, Gao, Kai, Giacca, Mauro, Zentilin, Lorena, Kleinschmidt, Juergen, Leuchs, Barbara, Müller, Marcus, Mizukami, Hiroaki, Ozawa, Keiya, Noordman, Yvet, Van Der Linden, Inge, Pythoud, Catherine, Tenenbaum, Liliane, Sumaroka, Marina, Wright, John Fraser, Zhang, Xinhua, Surosky, Richard, Weins, Brigitte, Snyder, Richard O., Ayuso, Eduard, Leon, Xavier, Bosch, Fatima, Blouin, Veronique, Darmon, Christophe, Moullier, Philippe, Lock, Martin, Alvira, Mauricio M.R., McGorray, Susan, Auricchio, Alberto, Doria, Monica, Bucher, Stephanie, Chtarto, Abdelwahed, Melas, Catherine, Bockstael, Olivier, Clark, Reed K.R., Fountain, Will, Gao, Guangping, Gao, Kai, Giacca, Mauro, Zentilin, Lorena, Kleinschmidt, Juergen, Leuchs, Barbara, Müller, Marcus, Mizukami, Hiroaki, Ozawa, Keiya, Noordman, Yvet, Van Der Linden, Inge, Pythoud, Catherine, Tenenbaum, Liliane, Sumaroka, Marina, Wright, John Fraser, Zhang, Xinhua, Surosky, Richard, Weins, Brigitte, and Snyder, Richard O.

Abstract

Gene therapy approaches using recombinant adeno-associated virus serotype 2 (rAAV2) and serotype 8 (rAAV8) have achieved significant clinical benefits. The generation of rAAV Reference Standard Materials (RSM) is key to providing points of reference for particle titer, vector genome titer, and infectious titer for gene transfer vectors. Following the example of the rAAV2RSM, here we have generated and characterized a novel RSM based on rAAV serotype 8. The rAAV8RSM was produced using transient transfection, and the purification was based on density gradient ultracentrifugation. The rAAV8RSM was distributed for characterization along with standard assay protocols to 16 laboratories worldwide. Mean titers and 95% confidence intervals were determined for capsid particles (mean, 5.50×1011 pt/ml; CI, 4.26×1011 to 6.75×1011 pt/ml), vector genomes (mean, 5.75×1011 vg/ml; CI, 3.05×1011 to 1.09×1012 vg/ml), and infectious units (mean, 1.26×109 IU/ml; CI, 6.46×108 to 2.51×109 IU/ml). Notably, there was a significant degree of variation between institutions for each assay despite the relatively tight correlation of assay results within an institution. This outcome emphasizes the need to use RSMs to calibrate the titers of rAAV vectors in preclinical and clinical studies at a time when the field is maturing rapidly. The rAAV8RSM has been deposited at the American Type Culture Collection (VR-1816) and is available to the scientific community., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2014

105. Telomerase expression confers cardioprotection in the adult mouse heart after acute myocardial infarction

Author

Bär, Christian, primary, de Jesus, Bruno Bernardes, additional, Serrano, Rosa, additional, Tejera, Agueda, additional, Ayuso, Eduard, additional, Jimenez, Veronica, additional, Formentini, Ivan, additional, Bobadilla, Maria, additional, Mizrahi, Jacques, additional, de Martino, Alba, additional, Gomez, Gonzalo, additional, Pisano, David, additional, Mulero, Francisca, additional, Wollert, Kai C., additional, Bosch, Fatima, additional, and Blasco, Maria A., additional

Published
2014
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106. Biochemical, histological and functional correction of mucopolysaccharidosis Type IIIB by intra-cerebrospinal fluid gene therapy

Author

Ribera, Albert, primary, Haurigot, Virginia, additional, Garcia, Miguel, additional, Marcó, Sara, additional, Motas, Sandra, additional, Villacampa, Pilar, additional, Maggioni, Luca, additional, León, Xavier, additional, Molas, Maria, additional, Sánchez, Víctor, additional, Muñoz, Sergio, additional, Leborgne, Christian, additional, Moll, Xavier, additional, Pumarola, Martí, additional, Mingozzi, Federico, additional, Ruberte, Jesús, additional, Añor, Sònia, additional, and Bosch, Fatima, additional

Published
2014
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107. Manufacturing and Characterization of a Recombinant Adeno-Associated Virus Type 8 Reference Standard Material

Author

Ayuso, Eduard, primary, Blouin, Véronique, additional, Lock, Martin, additional, McGorray, Susan, additional, Leon, Xavier, additional, Alvira, Mauricio R., additional, Auricchio, Alberto, additional, Bucher, Stephanie, additional, Chtarto, Abdelwahed, additional, Clark, K. Reed, additional, Darmon, Christophe, additional, Doria, Monica, additional, Fountain, Will, additional, Gao, Guangping, additional, Gao, Kai, additional, Giacca, Mauro, additional, Kleinschmidt, Juergen, additional, Leuchs, Barbara, additional, Melas, Catherine, additional, Mizukami, Hiroaki, additional, Müller, Marcus, additional, Noordman, Yvet, additional, Bockstael, Olivier, additional, Ozawa, Keiya, additional, Pythoud, Catherine, additional, Sumaroka, Marina, additional, Surosky, Richard, additional, Tenenbaum, Liliane, additional, van der Linden, Inge, additional, Weins, Brigitte, additional, Wright, J. Fraser, additional, Zhang, Xinhua, additional, Zentilin, Lorena, additional, Bosch, Fatima, additional, Snyder, Richard O., additional, and Moullier, Philippe, additional

Published
2014
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109. Sustained stimulation and expansion of Tregs by IL2 control autoimmunity without impairing immune responses to infection, vaccination and cancer

Author

Churlaud, Guillaume, primary, Jimenez, Veronica, additional, Ruberte, Jesus, additional, Amadoudji Zin, Martin, additional, Fourcade, Gwladys, additional, Gottrand, Gaelle, additional, Casana, Estefania, additional, Lambrecht, Benedicte, additional, Bellier, Bertrand, additional, Piaggio, Eliane, additional, Bosch, Fatima, additional, and Klatzmann, David, additional

Published
2014
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111. Proinsulin slows retinal degeneration and vision loss in the P23H rat model of retinitis pigmentosa

Author

Universidad de Alicante. Departamento de Fisiología, Genética y Microbiología, Fernández-Sánchez, Laura, Lax, Pedro, Isiegas, Carolina, Ayuso, Eduard, Ruiz Moreno, José María, Villa Polo, Pedro de la, Bosch, Fatima, Rosa Cano, Enrique J. de la, Cuenca, Nicolás, Universidad de Alicante. Departamento de Fisiología, Genética y Microbiología, Fernández-Sánchez, Laura, Lax, Pedro, Isiegas, Carolina, Ayuso, Eduard, Ruiz Moreno, José María, Villa Polo, Pedro de la, Bosch, Fatima, Rosa Cano, Enrique J. de la, and Cuenca, Nicolás

Abstract

Proinsulin has been characterized as a neuroprotective molecule. In this work we assess the therapeutic potential of proinsulin on photoreceptor degeneration, synaptic connectivity, and functional activity of the retina in the transgenic P23H rat, an animal model of autosomal dominant retinitis pigmentosa (RP). P23H homozygous rats received an intramuscular injection of an adeno-associated viral vector serotype 1 (AAV1) expressing human proinsulin (hPi+) or AAV1-null vector (hPi−) at P20. Levels of hPi in serum were determined by enzyme-linked immunosorbent assay (ELISA), and visual function was evaluated by electroretinographic (ERG) recording at P30, P60, P90, and P120. Preservation of retinal structure was assessed by immunohistochemistry at P120. Human proinsulin was detected in serum from rats injected with hPi+ at all times tested, with average hPi levels ranging from 1.1 nM (P30) to 1.4 nM (P120). ERG recordings showed an amelioration of vision loss in hPi+ animals. The scotopic b-waves were significantly higher in hPi+ animals than in control rats at P90 and P120. This attenuation of visual deterioration correlated with a delay in photoreceptor degeneration and the preservation of retinal cytoarchitecture. hPi+ animals had 48.7% more photoreceptors than control animals. Presynaptic and postsynaptic elements, as well as the synaptic contacts between photoreceptors and bipolar or horizontal cells, were preserved in hPi+ P23H rats. Furthermore, in hPi+ rat retinas the number of rod bipolar cell bodies was greater than in control rats. Our data demonstrate that hPi expression preserves cone and rod structure and function, together with their contacts with postsynaptic neurons, in the P23H rat. These data strongly support the further development of proinsulin-based therapy to counteract retinitis pigmentosa.

Published
2012

112. Relevance of an Academic GMP Pan-European Vector Infra-Structure (PEVI)

Author

Cohen-Haguenauer, Odile, Creff, N., Tunc, C., Cruz, Pedro Estilita P., Carrondo, Manuel, Aiuti, Alessandro, Montini, Eugenio, Baum, Christopher, Hildebrandt, Martin, Bosch, Fatima, Blomberg, Pontus, Gahrton, Gosta, Cichutek, Klaus, Schweizer, Matthias, Collins, Mary K L, Danos, Olivier, Dehaut, Frédéric, Tiberghien, Pierre, Federspiel, Mark, Galun, Eithan, Panet, Amos, Rasooly, Linda, Garritsen, Henk S P H., Hauser, Hansjörg, Klatzmann, David, Merten, Otto-Wilhelm, O'Brien, Timothy, Scherman, Daniel, Schmidt, Manfred, von Kalle, Christof, VandenDriessche, Thierry, Ziehr, Holger, Ylä-Herttuala, Seppo Pasi Antero S., Cohen-Haguenauer, Odile, Creff, N., Tunc, C., Cruz, Pedro Estilita P., Carrondo, Manuel, Aiuti, Alessandro, Montini, Eugenio, Baum, Christopher, Hildebrandt, Martin, Bosch, Fatima, Blomberg, Pontus, Gahrton, Gosta, Cichutek, Klaus, Schweizer, Matthias, Collins, Mary K L, Danos, Olivier, Dehaut, Frédéric, Tiberghien, Pierre, Federspiel, Mark, Galun, Eithan, Panet, Amos, Rasooly, Linda, Garritsen, Henk S P H., Hauser, Hansjörg, Klatzmann, David, Merten, Otto-Wilhelm, O'Brien, Timothy, Scherman, Daniel, Schmidt, Manfred, von Kalle, Christof, VandenDriessche, Thierry, Ziehr, Holger, and Ylä-Herttuala, Seppo Pasi Antero S.

Abstract

In the past 5 years, European investigators have played a major role in the development of clinical gene therapy. The provision of substantial funds by some individual member states to construct GMP facilities makes it an opportune time to network available gene therapy GMP facilities at an EU level. The integrated coordination of GMP production facilities and human skills for advanced gene and genetically-modified (GM) cell therapy, can dramatically enhance academic-led "First-in-man" gene therapy trials. Once proof of efficacy is gathered, technology can be transferred to the private sector which will take over further development taking advantage of knowledge and know-how. Complex technical challenges require existing production facilities to adapt to emerging technologies in a coordinated manner. These include a mandatory requirement for the highest quality of production translating gene-transfer technologies with pharmaceutical-grade GMP processes to the clinic. A consensus has emerged on the directions and priorities to adopt, applying to advanced technologies with improved efficacy and safety profiles, in particular AAV, lentivirus-based and oncolytic vectors. Translating cutting-edge research into "First-in-man" trials require that pre-normative research is conducted which aims to develop standard assays, processes and candidate reference materials. This research will help harmonise practices and quality in the production of GMP vector lots and GM-cells. In gathering critical expertise in Europe and establish conditions for interoperability, the PEVI infrastructure will contribute to the demands of the advanced therapy medicinal products* regulation and to both health and quality of life of EU-citizens. © 2010 Bentham Science Publishers Ltd., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2010

113. Characterization of a Recombinant Adeno-Associated Virus Type 2 Reference Standard Material.

Author

Lock, Martin, McGorray, Susan, Auricchio, Alberto, Ayuso, Eduard, Beecham, E Jeffery, Blouin, Veronique, Bosch, Fatima, Bose, Mahuya, Byrne, Barry, Caton, Tina, Chiorini, John A, Chtarto, Abdelwahed, Clark, K Reed, Conlon, Thomas, Darmon, Christophe, Doria, Monica, Douar, Anne-Marie, Flotte, Terence R, Francis, Joyce, Francois, Achille, Giacca, Mauro, Korn, Michael, Korytov, Irina, Leon, Xavier, Leuchs, Barbara, Lux, Gabriele, Melas, Catherine, Mizukami, Hiroaki, Moullier, Philippe, Muller, M, Ozawa, Keiya, Philipsberg, Tina, Poulard, Karine, Raupp, Christina, Riviere, Christelle, Roosendaal, Sigrid, Samulski, R Jude, Soltys, Steven, Surosky, R T, Tenenbaum, Liliane, Thomas, Darby L, van Montfort, Bart, Veres, Gabor, Wright, J Fraser, Xu, Yili, Zelenaia, Olga, Zentilin, Lorena, Snyder, Richard O, Lock, Martin, McGorray, Susan, Auricchio, Alberto, Ayuso, Eduard, Beecham, E Jeffery, Blouin, Veronique, Bosch, Fatima, Bose, Mahuya, Byrne, Barry, Caton, Tina, Chiorini, John A, Chtarto, Abdelwahed, Clark, K Reed, Conlon, Thomas, Darmon, Christophe, Doria, Monica, Douar, Anne-Marie, Flotte, Terence R, Francis, Joyce, Francois, Achille, Giacca, Mauro, Korn, Michael, Korytov, Irina, Leon, Xavier, Leuchs, Barbara, Lux, Gabriele, Melas, Catherine, Mizukami, Hiroaki, Moullier, Philippe, Muller, M, Ozawa, Keiya, Philipsberg, Tina, Poulard, Karine, Raupp, Christina, Riviere, Christelle, Roosendaal, Sigrid, Samulski, R Jude, Soltys, Steven, Surosky, R T, Tenenbaum, Liliane, Thomas, Darby L, van Montfort, Bart, Veres, Gabor, Wright, J Fraser, Xu, Yili, Zelenaia, Olga, Zentilin, Lorena, and Snyder, Richard O

Abstract

A recombinant adeno-associated virus serotype 2 Reference Standard Material (rAAV2 RSM) has been produced and characterized with the purpose of providing a reference standard for particle titer, vector genome titer, and infectious titer for AAV2 gene transfer vectors. Production and purification of the Reference Material were carried out using helper virus-free transient transfection and chromatographic purification. The purified bulk material was vialed, confirmed negative for microbial contamination and then distributed for characterization along with standard assay protocols and assay reagents to sixteen laboratories worldwide. Using statistical transformation and modeling of the raw data, mean titers and confidence intervals were determined for capsid particles ( :9.18 x 1011 particles/ml; 95% CI :7.89 x 1011 to 1.05 x 1012 particles/mL), vector genomes ( :3.28 x 1010 vg/ml; 95% CI :2.70 x 1010 to 4.75 x 1010 vg/ml), transducing units ( :5.09 x 108 TU/ml; 95% CI :2.00 x 108 to 9.60 x 108 TU/ml) and infectious units ( :4.37 x 109 TCID50IU/ml; 95% CI :2.06 x 109 to 9.26 x 109 TCID50 IU/ml). Further analysis confirmed the identity of the Reference Material as AAV2 and the purity relative to non-vector proteins as greater than 94%. One obvious trend in the quantitative data was the degree of variation between institutions for each assay despite the relatively tight correlation of assay results within an institution. This relatively poor degree of inter-laboratory precision and accuracy was apparent even though attempts were made to standardize the assays by providing detailed protocols and common reagents. This is the first time that such variation between laboratories has been thoroughly documented and the findings emphasize the need in the field for universal reference standards. The rAAV2 RSM has been deposited with the American Tissue Type Collection and is available to the scientific community to calibrate laboratory-specific internal titer standards., JOURNAL ARTICLE, SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2010

115. Adult Onset Global Loss of the Fto Gene Alters Body Composition and Metabolism in the Mouse

Author

McMurray, Fiona, primary, Church, Chris D., additional, Larder, Rachel, additional, Nicholson, George, additional, Wells, Sara, additional, Teboul, Lydia, additional, Tung, Y. C. Loraine, additional, Rimmington, Debra, additional, Bosch, Fatima, additional, Jimenez, Veronica, additional, Yeo, Giles S. H., additional, O'Rahilly, Stephen, additional, Ashcroft, Frances M., additional, Coll, Anthony P., additional, and Cox, Roger D., additional

Published
2013
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118. Targeting the association of calgranulin B (S100A9) with insulin resistance and type 2 diabetes

Author

Ortega, Francisco J., primary, Mercader, Josep M., additional, Moreno-Navarrete, José M., additional, Sabater, Mónica, additional, Pueyo, Neus, additional, Valdés, Sergio, additional, Ruiz, Bartomeu, additional, Luche, Elodie, additional, Naon, Deborah, additional, Ricart, Wifredo, additional, Botas, Patricia, additional, Delgado, Elias, additional, Burcelin, Remy, additional, Frühbeck, Gema, additional, Bosch, Fatima, additional, Mingrone, Gertrude, additional, Zorzano, Antonio, additional, and Fernández-Real, José M., additional

Published
2012
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119. Correction of Pathological Accumulation of Glycosaminoglycans in Central Nervous System and Peripheral Tissues of MPSIIIA Mice Through Systemic AAV9 Gene Transfer

Author

Ruzo, Albert, primary, Marcó, Sara, additional, García, Miquel, additional, Villacampa, Pilar, additional, Ribera, Albert, additional, Ayuso, Eduard, additional, Maggioni, Lucca, additional, Mingozzi, Federico, additional, Haurigot, Virginia, additional, and Bosch, Fatima, additional

Published
2012
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122. Liver Production of Sulfamidase Reverses Peripheral and Ameliorates CNS Pathology in Mucopolysaccharidosis IIIA Mice

Author

Ruzo, Albert, primary, Garcia, Miquel, additional, Ribera, Albert, additional, Villacampa, Pilar, additional, Haurigot, Virginia, additional, Marcó, Sara, additional, Ayuso, Eduard, additional, Anguela, Xavier M, additional, Roca, Carles, additional, Agudo, Judith, additional, Ramos, David, additional, Ruberte, Jesús, additional, and Bosch, Fatima, additional

Published
2012
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123. Protein Kinase C Delta (PKCδ) Affects Proliferation of Insulin-Secreting Cells by Promoting Nuclear Extrusion of the Cell Cycle Inhibitor p21Cip1/WAF1

Author

Ranta, Felicia, primary, Leveringhaus, Johannes, additional, Theilig, Dorothea, additional, Schulz-Raffelt, Gabriele, additional, Hennige, Anita M., additional, Hildebrand, Dominic G., additional, Handrick, René, additional, Jendrossek, Verena, additional, Bosch, Fatima, additional, Schulze-Osthoff, Klaus, additional, Häring, Hans-Ulrich, additional, and Ullrich, Susanne, additional

Published
2011
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126. Characterization of a Recombinant Adeno-Associated Virus Type 2 Reference Standard Material

Author

Lock, Martin, primary, McGorray, Susan, additional, Auricchio, Alberto, additional, Ayuso, Eduard, additional, Beecham, E. Jeffrey, additional, Blouin-Tavel, Véronique, additional, Bosch, Fatima, additional, Bose, Mahuya, additional, Byrne, Barry J., additional, Caton, Tina, additional, Chiorini, John A., additional, Chtarto, Abdelwahed, additional, Clark, K. Reed, additional, Conlon, Thomas, additional, Darmon, Christophe, additional, Doria, Monica, additional, Douar, Anne, additional, Flotte, Terence R., additional, Francis, Joyce D., additional, Francois, Achille, additional, Giacca, Mauro, additional, Korn, Michael T., additional, Korytov, Irina, additional, Leon, Xavier, additional, Leuchs, Barbara, additional, Lux, Gabriele, additional, Melas, Catherine, additional, Mizukami, Hiroaki, additional, Moullier, Philippe, additional, Müller, Marcus, additional, Ozawa, Keiya, additional, Philipsberg, Tina, additional, Poulard, Karine, additional, Raupp, Christina, additional, Rivière, Christel, additional, Roosendaal, Sigrid D., additional, Samulski, R. Jude, additional, Soltys, Steven M., additional, Surosky, Richard, additional, Tenenbaum, Liliane, additional, Thomas, Darby L., additional, van Montfort, Bart, additional, Veres, Gabor, additional, Wright, J. Fraser, additional, Xu, Yili, additional, Zelenaia, Olga, additional, Zentilin, Lorena, additional, and Snyder, Richard O., additional

Published
2010
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128. Overexpression of Kinase-Negative Protein Kinase Cδ in Pancreatic β-Cells Protects Mice From Diet-Induced Glucose Intolerance and β-Cell Dysfunction

Author

Hennige, Anita M., primary, Ranta, Felicia, additional, Heinzelmann, Isabel, additional, Düfer, Martina, additional, Michael, Diana, additional, Braumüller, Heidi, additional, Lutz, Stefan Z., additional, Lammers, Reiner, additional, Drews, Gisela, additional, Bosch, Fatima, additional, Häring, Hans-Ulrich, additional, and Ullrich, Susanne, additional

Published
2009
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131. Enforced expression of protein kinase C in skeletal muscle causes physical inactivity, fatty liver and insulin resistance in the brain

Author

Hennige, Anita M., primary, Heni, Martin, additional, Machann, Jürgen, additional, Staiger, Harald, additional, Sartorius, Tina, additional, Hoene, Miriam, additional, Lehmann, Rainer, additional, Weigert, Cora, additional, Peter, Andreas, additional, Bornemann, Antje, additional, Kroeber, Stefan, additional, Pujol, Anna, additional, Franckhauser, Sylvie, additional, Bosch, Fatima, additional, Schick, Fritz, additional, Lammers, Reiner, additional, and Häring, Hans-Ulrich, additional

Published
2008
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135. Overexpressing the novel autocrine/endocrine adipokine WISP2 induces hyperplasia of the heart, white and brown adipose tissues and prevents insulin resistance

Author

Grünberg, John R., Hoffmann, Jenny M., Hedjazifar, Shahram, Nerstedt, Annika, Jenndahl, Lachmi, Elvin, Johannes, Castellot, John, Wei, Lan, Movérare-Skrtic, Sofia, Ohlsson, Claes, Holm, Louise Mannerås, Bäckhed, Fredrik, Syed, Ismail, Bosch, Fatima, Saghatelian, Alan, Kahn, Barbara B., Hammarstedt, Ann, and Smith, Ulf

Abstract

WISP2 is a novel adipokine, most highly expressed in the adipose tissue and primarily in undifferentiated mesenchymal cells. As a secreted protein, it is an autocrine/paracrine activator of canonical WNT signaling and, as an intracellular protein, it helps to maintain precursor cells undifferentiated. To examine effects of increased WISP2 in vivo, we generated an aP2-WISP2 transgenic (Tg) mouse. These mice had increased serum levels of WISP2, increased lean body mass and whole body energy expenditure, hyperplastic brown/white adipose tissues and larger hyperplastic hearts. Obese Tg mice remained insulin sensitive, had increased glucose uptake by adipose cells and skeletal muscle in vivo and ex vivo, increased GLUT4, increased ChREBP and markers of adipose tissue lipogenesis. Serum levels of the novel fatty acid esters of hydroxy fatty acids (FAHFAs) were increased and transplantation of Tg adipose tissue improved glucose tolerance in recipient mice supporting a role of secreted FAHFAs. The growth-promoting effect of WISP2 was shown by increased BrdU incorporation in vivo and Tg serum increased mesenchymal precursor cell proliferation in vitro. In contrast to conventional canonical WNT ligands, WISP2 expression was inhibited by BMP4 thereby allowing normal induction of adipogenesis. WISP2 is a novel secreted regulator of mesenchymal tissue cellularity.

Published
2017
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140. Progressive neurologic and somatic disease in a novel mouse model of human mucopolysaccharidosis type IIIC

Author

Marcó, Sara, Pujol, Anna, Roca, Carles, Motas, Sandra, Ribera, Albert, Garcia, Miguel, Molas, Maria, Villacampa, Pilar, Melia, Cristian S., Sánchez, Víctor, Sánchez, Xavier, Bertolin, Joan, Ruberte, Jesús, Haurigot, Virginia, and Bosch, Fatima

Abstract

Mucopolysaccharidosis type IIIC (MPSIIIC) is a severe lysosomal storage disease caused by deficiency in activity of the transmembrane enzyme heparan-α-glucosaminide N-acetyltransferase (HGSNAT) that catalyses the N-acetylation of α-glucosamine residues of heparan sulfate. Enzyme deficiency causes abnormal substrate accumulation in lysosomes, leading to progressive and severe neurodegeneration, somatic pathology and early death. There is no cure for MPSIIIC, and development of new therapies is challenging because of the unfeasibility of cross-correction. In this study, we generated a new mouse model of MPSIIIC by targeted disruption of the Hgsnat gene. Successful targeting left LacZ expression under control of the Hgsnat promoter, allowing investigation into sites of endogenous expression, which was particularly prominent in the CNS, but was also detectable in peripheral organs. Signs of CNS storage pathology, including glycosaminoglycan accumulation, lysosomal distension, lysosomal dysfunction and neuroinflammation were detected in 2-month-old animals and progressed with age. Glycosaminoglycan accumulation and ultrastructural changes were also observed in most somatic organs, but lysosomal pathology seemed most severe in liver. Furthermore, HGSNAT-deficient mice had altered locomotor and exploratory activity and shortened lifespan. Hence, this animal model recapitulates human MPSIIIC and provides a useful tool for the study of disease physiopathology and the development of new therapeutic approaches.

Published
2016
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141. Telomerase gene therapy rescues telomere length, bone marrow aplasia, and survival in mice with aplastic anemia

Author

Bär, Christian, Povedano, Juan Manuel, Serrano, Rosa, Benitez-Buelga, Carlos, Popkes, Miriam, Formentini, Ivan, Bobadilla, Maria, Bosch, Fatima, and Blasco, Maria A.

Abstract

Aplastic anemia is a fatal bone marrow disorder characterized by peripheral pancytopenia and marrow hypoplasia. The disease can be hereditary or acquired and develops at any stage of life. A subgroup of the inherited form is caused by replicative impairment of hematopoietic stem and progenitor cells due to very short telomeres as a result of mutations in telomerase and other telomere components. Abnormal telomere shortening is also described in cases of acquired aplastic anemia, most likely secondary to increased turnover of bone marrow stem and progenitor cells. Here, we test the therapeutic efficacy of telomerase activation by using adeno-associated virus (AAV)9 gene therapy vectors carrying the telomerase Tert gene in 2 independent mouse models of aplastic anemia due to short telomeres (Trf1- and Tert-deficient mice). We find that a high dose of AAV9-Tert targets the bone marrow compartment, including hematopoietic stem cells. AAV9-Tert treatment after telomere attrition in bone marrow cells rescues aplastic anemia and mouse survival compared with mice treated with the empty vector. Improved survival is associated with a significant increase in telomere length in peripheral blood and bone marrow cells, as well as improved blood counts. These findings indicate that telomerase gene therapy represents a novel therapeutic strategy to treat aplastic anemia provoked or associated with short telomeres.

Published
2016
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