Arruebo, M. (Manuel)

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2016 - 20192

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    A simple approach to obtain hybrid Au-loaded polymeric nanoparticles with a tunable metal load
    (Royal Society of Chemistry, 2016) Sebastian, V. (Víctor); Blanco-Prieto, M.J. (María José); Arruebo, M. (Manuel); Larrea, A. (Ane); Imbuluzqueta, E. (Edurne); Santamaria-Ulecia, J.M. (Jesús Miguel); Luque-Michel, E. (Edurne); Lahuerta, C. (Celia)
    A new strategy to nanoengineer multi-functional polymer–metal hybrid nanostructures is reported. By using this protocol the hurdles of most of the current developments concerning covalent and noncovalent attachment of polymers to preformed inorganic nanoparticles (NPs) are overcome. The strategy is based on the in situ reduction of metal precursors using the polymeric nanoparticle as a nanoreactor. Gold nanoparticles and poly(DL-lactic-co-glycolic acid), PLGA, are located in the core and shell, respectively. This novel technique enables the production of PLGA NPs smaller than 200 nm that bear either a single encapsulated Au NP or several smaller NPs with tunable sizes and a 100% loading efficiency. In situ reduction of Au ions inside the polymeric NPs was achieved on demand by using heat to activate the reductive effect of citrate ions. In addition, we show that the loading of the resulting Au NPs inside the PLGA NPs is highly dependent on the surfactant used. Electron microscopy, laser irradiation, UV-Vis and fluorescence spectroscopy characterization techniques confirm the location of Au nanoparticles. These promising results indicate that these hybrid nanomaterials could be used in theranostic applications or as contrast agents in dark-field imaging and computed tomography
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    Liver expression of a MiniATP7B gene results in long-term restoration of copper homeostasis in a Wilson Disease Model in Mice
    (Wolters Kluwer, 2019) Murillo, O. (Oihana); Moreno-Luqui, D. (Daniel); Gazquez, C. (Cristina); Barberia, M. (Miren); Cenzano-Armendáriz, I. (Itziar); Navarro-Blasco, I. (Iñigo); Uriarte, I. (Iker); Sebastian, V. (Víctor); Arruebo, M. (Manuel); Ferrer, V. (Verónica); Bénichou, B. (Bernard); Combal, J.P. (Jean Philippe); Prieto, J. (Jesús); Hernández-Alcoceba, R. (Rubén); González-Aseguinolaza, G. (Gloria)
    Gene therapy with an adeno-associated vector (AAV) serotype 8 encoding the human ATPase copper-transporting beta polypeptide (ATP7B) complementary DNA (cDNA; AAV8-ATP7B) is able to provide long-term copper metabolism correction in 6-week-old male Wilson disease (WD) mice. However, the size of the genome (5.2 kilobases [kb]) surpasses the optimal packaging capacity of the vector, which resulted in low-yield production; in addition, further analyses in WD female mice and in animals with a more advanced disease revealed reduced therapeutic efficacy, as compared to younger males. To improve efficacy of the treatment, an optimized shorter AAV vector was generated, in which four out of six metal-binding domains (MBDs) were deleted from the ATP7B coding sequence, giving rise to the miniATP7B protein (Δ57-486-ATP7B). In contrast to AAV8-ATP7B, AAV8-miniATP7B could be produced at high titers and was able to restore copper homeostasis in 6- and 12-week-old male and female WD mice. In addition, a recently developed synthetic AAV vector, AAVAnc80, carrying the miniATP7B gene was similarly effective at preventing liver damage, restoring copper homeostasis, and improving survival 1 year after treatment. Transduction of approximately 20% of hepatocytes was sufficient to normalize copper homeostasis, suggesting that corrected hepatocytes are acting as a sink to eliminate excess of copper. Importantly, administration of AAVAnc80-miniATP7B was safe in healthy mice and did not result in copper deficiency. Conclusion: In summary, gene therapy using an optimized therapeutic cassette in different AAV systems provides long-term correction of copper metabolism regardless of sex or stage of disease in a clinically relevant WD mouse model. These results pave the way for the implementation of gene therapy in WD patients.