Pharmacological chaperone therapy for Gaucher disease: A patent review

Introduction: Mutations in the gene encoding for acid β-glucosidase (β-glucocerebrosidase, GlcCerase) are seen in Gaucher disease (GD), which give rise to significant protein misfolding effects and result in progressive accumulation of glucosyl ceramide. The main treatment for GD is enzyme replacement therapy (ERT). The iminosugar glycosidase inhibitor N-(n-butyl)-1-deoxynojirimycin (miglustat, Zavesca™) is used in a second treatment modality known as substrate reduction therapy. At the beginning of the 21st century, a third therapeutic paradigm was launched, namely, pharmacological chaperone therapy (PCT). This therapeutic strategy relies on the capability of such inhibitors to promote the correct folding and stabilize mutant forms of lysosomal enzymes, such as GlcCerase, as they pass through the secretory pathway. Areas covered: This review summarizes the different approaches used to implement the concept of PCT for GD. It discusses the relevant research, patents and patent applications filed in the last decade. Expert opinion: While the significance of PCT remains a matter of debate, the great interest gathered regarding it in a relatively few years reflects its broad potential scope, well beyond GD. The fact that pharmacological chaperones can be designed to cross the blood brain barrier (BBB) make them candidates for the treatment of neuronopathic forms of GD that are not responsive to ERT. Combined therapies offer even broader possibilities that deserve to be fully explored.Ministerio de Ciencia e Innovación CTQ2007-61180/PPQ, SAF2010-15670Junta de Andalucía P08-FQM-0371

Cyclodextrin-scaffolded glycotransporters for gene delivery

Abstract: Conventional drugs consist of a formulation of a bioactive species and a carrier, the former accounting for most of the sophistication of the design. In the case of biomolecular drugs, however, the role of the carrier becomes decisive in enabling the load to reach its target to carry out its designed therapeutic function. Thus, the clinical success of gene therapy, where the active principles are nucleic acids, critically depends on the use of efficient and safe delivery systems. Carbohydrates have proven particularly useful in this regard. Glycocoating, similarly to poly(ethylene)glycol (PEG)-coating (pegylation), can stabilize colloidal aggregates by improving solvation and preventing nonspecific interactions, for example, with serum proteins. Moreover, glycoconjugates can drive specific recognition and receptor-mediated internalization in target cells. Actually, the inherent flexibility of carbohydrate and glycoconjugate chemistry has greatly contributed to enlarging the range of functional materials that can be rationally conceived for gene delivery. Herein, this is illustrated with selected examples that focus on controlling the architectural parameters of the vectors to make them suitable for structure¿activity relationship (SAR) and optimization studies. The members of the cyclomaltooligosaccharide (cyclodextrin, CD) family will be the central actors of the story.Peer Reviewe

Harmonized tuning of nucleic acid and lectin binding properties with multivalent cyclodextrins for macrophage-selective gene delivery

Polycationic amphiphilic cyclodextrins (paCDs) have been shown to behave as efficient non-viral gene carriers paralleling the efficacy of commercial vectors towards a variety of cell lines. Their molecular framework and modular design allow the installation of saccharidic antennae to promote specific carbohydrate–protein interactions, thus potentially endowing them with selective targeting abilities. Yet, the presence of these additional functionalities onto the polycationic cluster may hamper paCD self-assembly and nucleic acid condensation. In this report we describe the influence of paCD mannosylation extent on paCD-pDNA nanocomplex stability as well as the consequences of varying glycotope density on mannose-specific lectin recognition and gene delivery capabilities. The work aims at exploring the potential of this approach to optimize both properties in order to modulate cell transfection selectivity.Ministerio de Economía y Competitividad SAF2013-44021-RJunta de Andalucía FQM-146

Uso del método de Split Bregman para la resolución del problema de compressed sensing en imagen de resonancia magnética dinámica cardiaca para pequeño animal

Actas de: XXIX Congreso Anual de la Sociedad Espñaola de Ingeniería Biomédica (CASEIB 2011). Cáceres, 16-18 Noviembre 2011.La imagen dinámica de resonancia magnética en pequeño animal es una herramienta muy importante en el estudio de enfermedades cardiovasculares. La reducción de los tiempos de adquisición de este tipo de imágenes es especialmente relevante para la obtención de imágenes de calidad con una buena resolución espacial y temporal. Actualmente existen diversas técnicas de aceleración que permiten reducir estos tiempos de adquisición, entre ellas la técnica de 'compressed sensing', en auge en los últimos años. Ésta técnica permite la reconstrucción de una imagen a partir de datos submuestreados mediante el uso de métodos de reconstrucción no lineales que minimizan la variación total de la imagen. Recientemente el método de Split Bregman ha demostrado ser computacionalmente eficiente para resolver este problema en imágenes de resonancia magnética. En este trabajo se amplía la metodología de Split Bregman para minimizar la variación total espacial y temporal en imágenes dinámicas, y se aplica a imágenes cardiacas de pequeño animal. Los resultados preliminares muestran que con la metodología propuesta es posible reducir el tiempo de adquisición hasta 5 veces manteniendo la calidad de imagen.Este trabajo ha sido financiado parcialmente por el Ministerio de Ciencia e Innovación (Red RECAVA) y la Comunidad de Madrid y los Fondos FEDER (proyecto ARTEMIS-S2009DPI-1802)Publicad

NMR study on the stabilization and chiral discrimination of sulforaphane enantiomers and analogues by cyclodextrins

Sulforaphane (SFN), a phytochemical isolated from broccoli, is an important antitumoral compound with additional beneficial effect on other important diseases. However, the chemical instability of SFN has hampered its clinical use. In order to circumvent this problem, we report the first comparative study on the inclusion complexes of SFN and SFN homologues with different cyclodextrins by NMR spectroscopy. From this study it has been shown that α-CD is the most indicated cyclodextrin for the stabilization of SFN and SFN homologues, and that the highest affinity constant is that of the isothiocyanate obtained from the wasabi. Furthermore, the study of the inclusion complexes of α-CD and the non-natural SFN and analogues with S absolute configuration at sulfur shows for the first time that α-CD is able to discriminate between the two enantiomers, with the natural R enantiomers forming the inclusion complexes with higher affinity.Ministerio de Economía yCompetitividad (grants No. CTQ2016-78580-C2-1-R, and CTQ2016-78580-C2-2-R)Junta de Andalucía (P11-FQM-8046)EvgenPharm

Solution blow spun graded dielectrics based on poly(vinylidene fluoride)/multi-walled carbon nanotubes nanocomposites

For the first time polymer-based graded nanocomposites were prepared by solution blow spinning, SBS, looking for new materials with optimal dielectric behavior. SBS was used as the processing method to apply layer by layer multi-walled carbon nanotubes, MWCNT, filled poly(vinylidene fluoride), PVDF, nanocomposites of well controlled compositions. Different configurations in terms of the disposition of layers with distinct concentration of MWCNT were considered. The structure, morphology and thermal behavior of the materials prepared were investigated so as their broadband dielectric properties in order to find and understand possible correlations. Morphological and slight structural changes were observed as a function of MWCNT concentration; however, they do not seem to be the main factors affecting the variations observed in the dielectric behavior of the materials under study. It was demonstrated that a particular design of PVDF based dielectrics, for which there is a particular gradient of MWCNT concentration, importantly increases the permittivity without increasing dielectric losses.The authors appreciate the financial support received from the Ministerio de Economía y Competitividad [MAT2014-59116-C2]; the Universidad Carlos III de Madrid due to Fondos de Investigación de Fco. Javier González Benito [2012/00130/004] and the strategic Action in Composites materials and interphases [2011/00287/002]. Finally, we greatly thank the help given by Dr. Gustavo González-Gaitano (Dept. Chemistry, University of Navarra) conducting an extraordinary work with FTIR spectroscopy

Effect of different interpolation methods on the accuracy of the reconstruction of spiral k-space trajectories in MRI

[Poster] 4th European Molecular Imaging Meeting, Barcelona, Spain, May 27 - 30, 2009This work is supported in part by the projects CdTeaM (CeniT-ingenio 2010), Ministerio de Ciencia e innovación, and Ciber Cb07/09/0031 CiberSaM, Ministerio de Sanidad y Consumo.Publicad

Sobre la medida del tamaño del terremoto y la peligrosidad sísmica en España/ On earthquake size measures and seismic hazard in Spain

The influence of earthquake size parameters contained on seismic catalogues on seismic hazard assessment studies is discussed. The topic is illustrated in the Spanish context, characterized by moderate seismic activity and consequently, limited availability of seismic data. The different objectives pursued by seismic catalogue providers and users (in this case, earthquake hazard analysts) may cause misunderstandings and possibly misuses of catalogued size parameters. As an example, it is shown that magnitude data sets should be treated separately depending on the geographic area considered. Accordingly, region-dependent correlations between magnitude scales, required for implementing seismic hazard analyses, are presented. Results of this work underline the need of composing earthquake catalogues with homogeneous earthquake size parameters not only for historical events, but also for recent and future ones

Micrometric control of the optics of the human eye: environment or genes?

Purpose: The human eye has typically more optical aberrations than conventional artificial optical systems. While the lower order modes (defocus and astigmatism) are well studied, our purpose is to explore the influence of genes versus the environment on the higher order aberrations of the optical components of the eye. Methods: We have performed a classical twin study in a sample from the Region of Murcia (Spain). Optical aberrations using a Hartmann-Shack sensor (AOnEye Voptica SL, Murcia, Spain) and corneal aberrations (using corneal topography data) were measured in 138 eyes corresponding to 69 twins; 36 monozygotic (MZ) and 33 dizygotic (DZ) pairs (age 55 years, SD 7 years). Intraclass correlation coefficients (ICCs) were used to estimate how strongly aberrations of twins resemble each other, and genetic models were fitted to quantify heritability in the selected phenotypes. Results: Genes had a significant influence in the variance of most of the higher order aberration terms (heritability from 40% to 70%). This genetic influence was observed similarly in both cornea and complete eye aberrations. Additionally, the compensation factor of spherical aberration in the eye (i.e., how much corneal spherical aberration was compensated by internal spherical aberration) was found under genetic influence (heritability of 68%). Conclusions: There is a significant genetic contribution to the variance of aberrations of the eye, not only at macroscopic levels, as in myopia or astigmatism, but also at microscopic levels, where a few micrometers changes in surface topography can produce a large difference in the value of the optical aberrations