Targeting Innate Immunity with dsRNA-Conjugated Mesoporous Silica Nanoparticles Promotes Antitumor Effects on Breast Cancer Cells

The authors describe herein a Toll-like receptor 3 (TLR3) targeting delivery system based on mesoporous silica nanoparticles capped with the synthetic double stranded RNA polyinosinic-polycytidylic acid (poly(I:C)) for controlled cargo delivery in SK-BR-3 breast carcinoma cells. The authors' results show that poly(I:C)-conjugated nanoparticles efficiently targeted breast cancer cells due to dsRNA-TLR3 interaction. Such interaction also triggered apoptotic pathways in SK-BR-3, significantly decreasing cells viability. Poly(I:C) cytotoxic effect in breast carcinoma cells was enhanced by loading nanoparticles' mesopores with the anthracyclinic antibiotic doxorubicin, a commonly used chemotherapeutic agent.We thank the Spanish Government (projects SAF2010-21195 and MAT2012-38429-C04-01) and the Generalitat Valenciana (project PROMETEOII/2014/047) for support. A.U. and C.G. are grateful to the Ministry of Education, Culture and Sport for their doctoral fellowships. We thank J. M. 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Gated mesoporous silica nanoparticles for the controlled delivery of drugs in cancer cells

In recent years, mesoporous silica nanoparticles (MSNs) have been used as effective supports for the development of controlled-release nanodevices that are able to act as multifunctional delivery platforms for the encapsulation of therapeutic agents, enhancing their bioavailability and overcoming common issues such as poor water solubility and poor stability of some drugs. In particular, redox-responsive delivery systems have attracted the attention of scientists because of the intracellular reductive environment related to a high concentration of glutathione (GSH). In this context, we describe herein the development of a GSH-responsive delivery system based on poly(ethylene glycol)- (PEG-) capped MSNs that are able to deliver safranin O and doxorubicin in a controlled manner. The results showed that the PEG-capped systems designed in this work can be maintained closed at low GSH concentrations, yet the cargo can be delivered when the concentration of GSH is increased. Moreover, the efficacy of the PEG-capped system in delivering the cytotoxic agent doxorubicin in cells was also demonstrated.The authors thank the Spanish Government (Project MAT2012-38429-C04-01), the Generalitat Valenciana (Project PROMETEOII/2014/047), and the Universitat Politecnica de Valencia (Project SP20120795) for support. C.G. and C.d.l.T also thank the Spanish Ministry of Education for their FPU grants. The authors also thank UPV electron microscopy and CIPF confocal microscopy services for technical support.Giménez Morales, C.; De La Torre, C.; Gorbe, M.; Aznar, E.; Sancenón Galarza, F.; Murguía, JR.; Martínez-Máñez, R.... (2015). Gated mesoporous silica nanoparticles for the controlled delivery of drugs in cancer cells. Langmuir. 31(12):3753-3762. https://doi.org/10.1021/acs.langmuir.5b00139S37533762311

Encapsulation of folic acid in different silica porous supports: A comparative study

Although folic acid is essential to numerous bodily functions, recent research indicates that a massive exposition to the vitamin could be a double-edged sword. In this study, the capacity of different caped mesoporous silica particles (i.e. Hollow Silica Shells, MCM-41, SBA-15 and UVM-7) to dose FA during its passage through the gastrointestinal tract has been evaluated. Results confirmed that the four capped materials were capable to hinder the delivery of FA at low pH (i.e. stomach) as well as able to deliver great amounts of the vitamin at neutral pH (i.e. intestine). Nevertheless, the encapsulation efficiency and the deliver kinetics differed among supports. While supports with large pore entrance exhibited an initial fast release, MCM-41, showed a sustained release along the time. This correlation between textural properties and release kinetics for each of the supports reveals the importance of a proper support selection as a strategy to control the delivery of active molecules.Authors gratefully acknowledge the financial support from the Ministerio de Economia y Competitividad (Projects AGL2012-39597-C02-01, AGL2012-39597-C02-02 and MAT2012-38429-C04-01) and the Generalitat Valenciana (project PROMETEO/2009/016). E.P. and M.R. are grateful to the Ministerio de Ciencia e Innovacion for their Grants (AP2008-00620, AP2010-4369). Electron Microscopy Service of the UPV is also acknowledged.Pérez-Esteve, É.; Ruiz Rico, M.; De La Torre Paredes, C.; Villaescusa Alonso, LA.; Sancenón Galarza, F.; Marcos Martínez, MD.; Amoros Del Toro, PJ.... (2016). Encapsulation of folic acid in different silica porous supports: A comparative study. Food Chemistry. 196:66-75. https://doi.org/10.1016/j.foodchem.2015.09.017S667519

Fluorogenic detection of Tetryl and TNT explosives using nanoscopic-capped mesoporous hybrid materials

[EN] A hybrid capped mesoporous material, which was selectively opened in the presence of Tetryl and TNT, has been synthesised and used for the fluorogenic recognition of these nitroaromatic explosives.Financial support from the Spanish Government (project MAT2012-38429-C04-01) and the Generalitat Valencia (project PROMETEO/2009/016) is gratefully acknowledged. Y.S. and E.P. are grateful to the Spanish Ministry of Science and Innovation for their grants. A. A. also thanks the Generalitat Valenciana for his Santiago Grisolia fellowship.Salinas Soler, Y.; Agostini, A.; Pérez Esteve, E.; Martínez Mañez, R.; Sancenón Galarza, F.; Marcos Martínez, MD.; Soto Camino, J.... (2013). Fluorogenic detection of Tetryl and TNT explosives using nanoscopic-capped mesoporous hybrid materials. Journal of Materials Chemistry. 1(11):3561-3564. https://doi.org/10.1039/C3TA01438JS35613564111Singh, S. (2007). Sensors—An effective approach for the detection of explosives. 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Detection of explosive vapors with a charge transfer molecule: self-assembly assisted morphology tuning and enhancement in sensing efficiency. Chemical Communications, 46(6), 874. doi:10.1039/b921520dSalinas, Y., Climent, E., Martínez-Máñez, R., Sancenón, F., Marcos, M. D., Soto, J., … Pérez de Diego, A. (2011). Highly selective and sensitive chromo-fluorogenic detection of the Tetryl explosive using functional silica nanoparticles. Chemical Communications, 47(43), 11885. doi:10.1039/c1cc14877jCliment, E., Martínez-Máñez, R., Sancenón, F., Marcos, M. D., Soto, J., Maquieira, A., & Amorós, P. (2010). Controlled Delivery Using Oligonucleotide-Capped Mesoporous Silica Nanoparticles. Angewandte Chemie International Edition, 49(40), 7281-7283. doi:10.1002/anie.201001847Climent, E., Marcos, M. D., Martínez-Máñez, R., Sancenón, F., Soto, J., Rurack, K., & Amorós, P. (2009). The Determination of Methylmercury in Real Samples Using Organically Capped Mesoporous Inorganic Materials Capable of Signal Amplification. Angewandte Chemie International Edition, 48(45), 8519-8522. doi:10.1002/anie.200904243Climent, E., Bernardos, A., Martínez-Máñez, R., Maquieira, A., Marcos, M. D., Pastor-Navarro, N., … Amorós, P. (2009). Controlled Delivery Systems Using Antibody-Capped Mesoporous Nanocontainers. Journal of the American Chemical Society, 131(39), 14075-14080. doi:10.1021/ja904456dCabrera, S., El Haskouri, J., Guillem, C., Latorre, J., Beltrán-Porter, A., Beltrán-Porter, D., … Amorós *, P. (2000). Generalised syntheses of ordered mesoporous oxides: the atrane route. Solid State Sciences, 2(4), 405-420. doi:10.1016/s1293-2558(00)00152-7Kolb, H. C., Finn, M. G., & Sharpless, K. B. (2001). Click Chemistry: Diverse Chemical Function from a Few Good Reactions. 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Oligonucleotide-capped mesoporous silica nanoparticles as DNA-responsive dye delivery systems for genomic DNA detection

[EN] New hybrid oligonucleotide-capped mesoporous silica nanoparticles able to detect genomic DNA were designed.Financial support from the Spanish Government (Project MAT2012-38429-C04) and the Generalitat Valencia (Project PROMETEOII/2014/047) is gratefully acknowledged. Ll. P. is grateful to the Universidad Politecnica de Valencia for his grant.Pascual Vidal, L.; Baroja, I.; Aznar Gimeno, E.; Sancenón Galarza, F.; Marcos Martínez, MD.; Murguía Ibáñez, JR.; Amoros Del Toro, PJ.... (2015). Oligonucleotide-capped mesoporous silica nanoparticles as DNA-responsive dye delivery systems for genomic DNA detection. Chemical Communications. 51(8):1414-1416. https://doi.org/10.1039/C4CC08306GS14141416518Agostini, A., Mondragón, L., Bernardos, A., Martínez-Máñez, R., Marcos, M. D., Sancenón, F., … Murguía, J. R. (2012). Targeted Cargo Delivery in Senescent Cells Using Capped Mesoporous Silica Nanoparticles. Angewandte Chemie International Edition, 51(42), 10556-10560. doi:10.1002/anie.201204663Zhang, Q., Wang, X., Li, P.-Z., Nguyen, K. T., Wang, X.-J., Luo, Z., … Zhao, Y. (2013). Biocompatible, Uniform, and Redispersible Mesoporous Silica Nanoparticles for Cancer-Targeted Drug Delivery In Vivo. Advanced Functional Materials, 24(17), 2450-2461. doi:10.1002/adfm.201302988Chen, C., Geng, J., Pu, F., Yang, X., Ren, J., & Qu, X. (2010). Polyvalent Nucleic Acid/Mesoporous Silica Nanoparticle Conjugates: Dual Stimuli-Responsive Vehicles for Intracellular Drug Delivery. Angewandte Chemie International Edition, 50(4), 882-886. doi:10.1002/anie.201005471Zhou, L., Chen, Z., Dong, K., Yin, M., Ren, J., & Qu, X. (2013). DNA-mediated Construction of Hollow Upconversion Nanoparticles for Protein Harvesting and Near-Infrared Light Triggered Release. Advanced Materials, 26(15), 2424-2430. doi:10.1002/adma.201304437Agostini, A., Mondragón, L., Pascual, L., Aznar, E., Coll, C., Martínez-Máñez, R., … Gil, S. (2012). Design of Enzyme-Mediated Controlled Release Systems Based on Silica Mesoporous Supports Capped with Ester-Glycol Groups. Langmuir, 28(41), 14766-14776. doi:10.1021/la303161eColl, C., Bernardos, A., Martínez-Máñez, R., & Sancenón, F. (2012). Gated Silica Mesoporous Supports for Controlled Release and Signaling Applications. Accounts of Chemical Research, 46(2), 339-349. doi:10.1021/ar3001469Climent, E., Martínez-Máñez, R., Maquieira, Á., Sancenón, F., Marcos, M. D., Brun, E. M., … Amorós, P. (2012). Antibody-Capped Mesoporous Nanoscopic Materials: Design of a Probe for the Selective Chromo-Fluorogenic Detection of Finasteride. ChemistryOpen, 1(6), 251-259. doi:10.1002/open.201100008Oroval, M., Climent, E., Coll, C., Eritja, R., Aviñó, A., Marcos, M. D., … Amorós, P. (2013). An aptamer-gated silica mesoporous material for thrombin detection. Chemical Communications, 49(48), 5480. doi:10.1039/c3cc42157kChen, M., Huang, C., He, C., Zhu, W., Xu, Y., & Lu, Y. (2012). A glucose-responsive controlled release system using glucose oxidase-gated mesoporous silica nanocontainers. Chemical Communications, 48(76), 9522. doi:10.1039/c2cc34290aCliment, E., Martínez-Máñez, R., Sancenón, F., Marcos, M. D., Soto, J., Maquieira, A., & Amorós, P. (2010). Controlled Delivery Using Oligonucleotide-Capped Mesoporous Silica Nanoparticles. Angewandte Chemie International Edition, 49(40), 7281-7283. doi:10.1002/anie.201001847Climent, E., Mondragón, L., Martínez-Máñez, R., Sancenón, F., Marcos, M. D., Murguía, J. R., … Pérez-Payá, E. (2013). Selective, Highly Sensitive, and Rapid Detection of Genomic DNA by Using Gated Materials:MycoplasmaDetection. Angewandte Chemie International Edition, 52(34), 8938-8942. doi:10.1002/anie.201302954Zhang, Z., Balogh, D., Wang, F., Sung, S. Y., Nechushtai, R., & Willner, I. (2013). Biocatalytic Release of an Anticancer Drug from Nucleic-Acids-Capped Mesoporous SiO2 Using DNA or Molecular Biomarkers as Triggering Stimuli. ACS Nano, 7(10), 8455-8468. doi:10.1021/nn403772jWu, L., Ren, J., & Qu, X. (2014). Target-responsive DNA-capped nanocontainer used for fabricating universal detector and performing logic operations. Nucleic Acids Research, 42(21), e160-e160. doi:10.1093/nar/gku858Drexler, H. G., & Uphoff, C. C. (2002). Cytotechnology, 39(2), 75-90. doi:10.1023/a:1022913015916Matas Andreu, L., Molinos Abós, S., Fernández Rivas, G., González Soler, V., & Ausina Ruiz, V. (2006). Diagnóstico serológico de las infecciones por Mycoplasma pneumoniae. Enfermedades Infecciosas y Microbiología Clínica, 24, 19-23. doi:10.1157/13094274V. Ausina , Infecciones causadas por micoplasmas, Medicina Interna, Elsevier España, 2004, 15th edn, pp. 2363–236

Enhanced antifungal efficacy of tebuconazole using gated pH-driven mesoporous nanoparticles

pH-sensitive gated mesoporous silica nanoparticles have been synthesized. Increased extracellular pH and internalization into living yeast cells triggered molecular gate aperture and cargo release. Proper performance of the system was demonstrated with nanodevices loaded with fluorescein or with the antifungal agent tebuconazole. Interestingly, nanodevices loaded with tebuconazole significantly enhanced tebuconazole cytotoxicity. As alterations of acidic external pH are a key parameter in the onset of fungal vaginitis, this nanodevice could improve the treatment for vaginal mycoses.Mas Font, N.; Galiana, I.; Hurtado, S.; Mondragón Martínez, L.; Bernardos Bau, A.; Sancenón Galarza, F.; Marcos Martínez, MD.... (2014). Enhanced antifungal efficacy of tebuconazole using gated pH-driven mesoporous nanoparticles. International Journal of Nanomedicine. 9:2597-2606. doi:10.2147/IJN.S59654S25972606

Poly(N-isopropylacrylamide)-gated Fe3O4/SiO2 core shell nanoparticles with expanded mesoporous structures for the temperature triggered release of lysozyme

Core-shell nanoparticles comprised of Fe3O4 cores and a mesoporous silica shell with an average expanded pore size of 6.07 nm and coated with a poly(N-isopropylacrylamide) (PNIPAM) layer (CS MSNs EP PNIPAM) were prepared and characterized. The nanoparticles was loaded with (Ru(bipy)3 2+) dye or an antibacterial enzyme, lysozyme, to obtain CS MSNs EP PNIPAM Ru(bipy)3 2+ and CS MSNs EP PNIPAM Lys, respectively. The lysozyme loading was determined to be 160 mg/g of nanoparticle. It was seen that Ru(bipy)3 2+ and lysozyme release was minimal at a room temperature of 25 ºC while at physiological temperature (37 º C), abrupt release was observed. The applicability of the CS MSNs EP PNIPAM Lys was further tested with two Gram-positive bacteria samples, Bacillus cereus and Micrococcus luteus. At physiological temperature, the nanoparticles were shown to reduce bacterial growth, indicating a successful release of lysozyme from the nanoparticles. This nanoparticle system shows potential as a nanocarrier for the loading of similarly sized proteins or other species as a drug delivery platform.The authors wish to express their gratitude to the facilities at Ciudad Politecnica de la Innovacion (CPI), El Centro de Reconocimiento Molecular y Desarrollo Tecnologico (IDM), the Biotechnology Department at UPV, and the Instituto de Biologia Molecular y Celular de Plantas (IBMCP) at UPV for assistance in the materials characterization techniques and for providing the bacterial samples for antibacterial testing. Warm thanks are given to the Transatlantic Partnership for Excellence in Engineering (TEE) program, an Erasmus Mundus-Action 2 project by the European Commission, for the opportunity to undertake research at the collaborating university, UPV. The University of California Office of the President (UCOP) Lab Fees Research Program funded this research. The authors also thank the Spanish Government (Projects MAT2012-38429-C04-01 and MAT2012-38429-C04-03), the Generalitat Valenciana (Project PROMETEOII/2014/047) for support.Yu, E.; Galiana, I.; Martínez-Máñez, R.; Stroeve, P.; Marcos Martínez, MD.; Aznar, E.; Sancenón Galarza, F.... (2015). Poly(N-isopropylacrylamide)-gated Fe3O4/SiO2 core shell nanoparticles with expanded mesoporous structures for the temperature triggered release of lysozyme. Colloids and Surfaces B: Biointerfaces. 135:652-660. https://doi.org/10.1016/j.colsurfb.2015.06.048S65266013

Towards Chemical Communication between Gated Nanoparticles

The design of comparatively simple and modularly configurable artificial systems able to communicate through the exchange of chemical messengers is, to the best of our knowledge, an unexplored field. As a proof-of-concept, we present here a family of nanoparticles that have been designed to communicate with one another in a hierarchical manner. The concept involves the use of capped mesoporous silica supports in which the messenger delivered by a first type of gated nanoparticle is used to open a second type of nanoparticle, which delivers another messenger that opens a third group of gated nanoobjects.We believe that the conceptual idea that nanodevices can be designed to communicate with one another may result in novel applications and will boost further advances towards cooperative systems with complex behavior as a result of the communication between simple abiotic individual components.Financial support from the Spanish government (project MAT2012-38429-C04-01) and the Generalitat Valencia (project PROMETEO/2009/016) is gratefully acknowledged. E.A. thanks the Universitat Politecnica de Valencia (project SP20120795) for support. C.G. is grateful to the Spanish Ministry of Science and Innovation for a grant. E.C. is grateful to the Adolf-Martens-Fonds for a fellowship. We are indebted to M. Dinter (LTB Lasertechnik Berlin GmbH) for assistance with the graphics.Giménez Morales, C.; Climent Terol, E.; Aznar Gimeno, E.; Martínez Mañez, R.; Sancenón Galarza, F.; Marcos Martínez, MD.; Amoros Del Toro, PJ.... (2014). Towards Chemical Communication between Gated Nanoparticles. Angewandte Chemie International Edition. 53(46):12629-12633. https://doi.org/10.1002/anie.201405580S12629126335346Steiger, S., Schmitt, T., & Schaefer, H. M. (2010). The origin and dynamic evolution of chemical information transfer. Proceedings of the Royal Society B: Biological Sciences, 278(1708), 970-979. doi:10.1098/rspb.2010.2285Waters, C. M., & Bassler, B. L. (2005). QUORUM SENSING: Cell-to-Cell Communication in Bacteria. Annual Review of Cell and Developmental Biology, 21(1), 319-346. doi:10.1146/annurev.cellbio.21.012704.131001Van Donk, E. (2007). Chemical information transfer in freshwater plankton. Ecological Informatics, 2(2), 112-120. doi:10.1016/j.ecoinf.2007.03.002Robinson, G. 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M., Wells, C. A., & Hamm, H. E. (2012). GPCR mediated regulation of synaptic transmission. Progress in Neurobiology, 96(3), 304-321. doi:10.1016/j.pneurobio.2012.01.009Aznar, E., Martínez-Máñez, R., & Sancenón, F. (2009). Controlled release using mesoporous materials containing gate-like scaffoldings. Expert Opinion on Drug Delivery, 6(6), 643-655. doi:10.1517/17425240902895980Cotí, K. K., Belowich, M. E., Liong, M., Ambrogio, M. W., Lau, Y. A., Khatib, H. A., … Stoddart, J. F. (2009). Mechanised nanoparticles for drug delivery. Nanoscale, 1(1), 16. doi:10.1039/b9nr00162jWang, C., Li, Z., Cao, D., Zhao, Y.-L., Gaines, J. W., Bozdemir, O. A., … Stoddart, J. F. (2012). Stimulated Release of Size-Selected Cargos in Succession from Mesoporous Silica Nanoparticles. Angewandte Chemie International Edition, 51(22), 5460-5465. doi:10.1002/anie.201107960Wang, C., Li, Z., Cao, D., Zhao, Y.-L., Gaines, J. W., Bozdemir, O. A., … Stoddart, J. F. (2012). 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Hydrolysis of DCNP (a Tabun mimic) catalyzed by mesoporous silica nanoparticles

[EN] The hydrolysis of diethylcyanophosphonate, DCNP (a Tabun simulant) in the presence of mesoporous silica nanoparticles (MSN) has been studied in acetonitrile:water (99.5:0.5 v/v) mixtures using 31P NMR as a suitable technique to follow the DCNP hydrolysis. MSN alone was not capable to induce DCNP hydrolysis, yet MSN in combination with the presence of the bases potassium carbonate, triethylamine or DABCO enhanced DCNP degradation. When MSN was used combined with K2CO3, a hydrolysis of ca. 95% of the initial DCNP after 60 min was observed. In the presence of DABCO, MSN was able to induce the hydrolysis of ca. 90% of DCNP after the same time. However, the DCNP hydrolysis using MSN in the presence of Et3N was lower (ca. 30%). In the absence of nanoparticles, DCNP hydrolysis reached only ca. 30% for K2CO3 and DABCO and ca. 7% for Et3N after 60 min. Moreover, kinetic studies were also carried out with the use of solids MSN-1 and MSN-2 that were obtained by reaction of MSN with K2CO3 or DABCO. After the reaction the solids were isolated by centrifugation, washed with acetonitrile and dried. MSN-1 was able to hydrolyse DCNP in a similar way to that found with the MSN-K2CO3 mixture. However, MSN-2 nanoparticles induced a very low DCNP hydrolysis. From all these studies it was found that the main product of the DCNP hydrolysis is tetraethylpyrophosphate. The presence of diethyl phosphoric acid was also observed but at very low concentration. From kinetic data a catalytic mechanism is proposedThis research was supported by the Ministerio de Educacion y Ciencia (MAT2012-38429-C04). SCSIE (Universidad de Valencia) is gratefully acknowledged for all the equipment employed.Candel Busquets, I.; Marcos Martínez, MD.; Martínez-Máñez, R.; Sancenón Galarza, F.; Costero, AM.; Parra Álvarez, M.; Gil Grau, S.... (2015). Hydrolysis of DCNP (a Tabun mimic) catalyzed by mesoporous silica nanoparticles. Microporous and Mesoporous Materials. 217:30-38. doi:10.1016/j.micromeso.2015.05.041S303821

X chromosome inactivation does not necessarily determine the severity of the phenotype in Rett syndrome patients

WOS: 000481590200024PubMed ID: 31427717Rett syndrome (RTT) is a severe neurological disorder usually caused by mutations in the MECP2 gene. Since the MECP2 gene is located on the X chromosome, X chromosome inactivation (XCI) could play a role in the wide range of phenotypic variation of RTT patients; however, classical methylation-based protocols to evaluate XCI could not determine whether the preferentially inactivated X chromosome carried the mutant or the wild-type allele. Therefore, we developed an allele-specific methylation-based assay to evaluate methylation at the loci of several recurrent MECP2 mutations. We analyzed the XCI patterns in the blood of 174 RTT patients, but we did not find a clear correlation between XCI and the clinical presentation. We also compared XCI in blood and brain cortex samples of two patients and found differences between XCI patterns in these tissues. However, RTT mainly being a neurological disease complicates the establishment of a correlation between the XCI in blood and the clinical presentation of the patients. Furthermore, we analyzed MECP2 transcript levels and found differences from the expected levels according to XCI. Many factors other than XCI could affect the RTT phenotype, which in combination could influence the clinical presentation of RTT patients to a greater extent than slight variations in the XCI pattern.Spanish Ministry of Health (Instituto de Salud Carlos III/FEDER) [PI15/01159]; Crowdfunding program PRECIPITA, from the Spanish Ministry of Health (Fundacion Espanola para la Ciencia y la Tecnologia); Catalan Association for Rett Syndrome; Fondobiorett; Mi Princesa RettWe thank all patients and their families who contributed to this study. The work was supported by grants from the Spanish Ministry of Health (Instituto de Salud Carlos III/FEDER, PI15/01159); Crowdfunding program PRECIPITA, from the Spanish Ministry of Health (Fundacion Espanola para la Ciencia y la Tecnologia); the Catalan Association for Rett Syndrome; Fondobiorett and Mi Princesa Rett