Solid lipid nanoparticle-based vectors intended for the treatment of X-linked juvenile retinoschisis by gene therapy: In vivo approaches in Rs1h-deficient mouse model

Apaolaza, Paola S.; Pozo-Rodríguez, Ana del; Torrecilla, Josune; Rodríguez-Gascón, Alicia; Rodríguez, Juan Manuel; Friedrich, Ulrike; Weber, Bernhard H. F.; Solinís, Maria Ángelés

doi:10.1016/j.jconrel.2015.09.033

Cited by 48 publications

(39 citation statements)

References 36 publications

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“…The protamine has shown to increase the transfection efficacy of non-viral vectors due to its high ability to condense the genetic material, and therefore, to protect it from degradation, facilitate the entry into the nucleus, and to enhance transcription [32,33,34]. A polysaccharide, dextran, was also included because it is biocompatible and has demonstrated to contribute to nucleic acid delivery; moreover, it shows low cytotoxicity, is easily subject to chemical modification, have stealth properties, and is widely used for pharmaceutical and biomedical applications [35,36]. For the formation of the vectors, the complex dextran-protamine-plasmid is adsorbed on the nanoparticle surface, playing the electrostatic interactions between the components a fundamental role.…”

Section: Discussionmentioning

confidence: 99%

MMP-9 Downregulation with Lipid Nanoparticles for Inhibiting Corneal Neovascularization by Gene Silencing

et al. 2019

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Gene silencing targeting proangiogenic factors have been shown to be a useful strategy in the treatment of corneal neovascularization (CNV). Among interference RNA (RNAi) molecules, short-hairpin RNA (shRNA) is a plasmid-coded RNA able to down-regulate the expression of the desired gene. It is continuously produced in the host cell, inducing a durable gene silencing effect. The aim of this work was to develop a solid lipid nanoparticle (SLN)-based shRNA delivery system to downregulate metalloproteinase 9 (MMP-9), a proangiogenic factor, in corneal cells for the treatment of CNV associated with inflammation. The nanovectors were prepared using a solvent emulsification-evaporation technique, and after physicochemical evaluation, they were evaluated in different culture cell models. Transfection efficacy, cell internalization, cell viability, the effect on MMP-9 expression, and cell migration were evaluated in human corneal epithelial cells (HCE-2). The inhibition of tube formation using human umbilical vein endothelial cells (HUVEC) was also assayed. The non-viral vectors based on SLN were able to downregulate the MMP-9 expression in HCE-2 cells via gene silencing, and, consequently, to inhibit cell migration and tube formation. These results demonstrate the potential of lipid nanoparticles as gene delivery systems for the treatment of CNV-associated inflammation by RNAi technology.

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Section: Discussionmentioning

confidence: 99%

MMP-9 Downregulation with Lipid Nanoparticles for Inhibiting Corneal Neovascularization by Gene Silencing

et al. 2019

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“…Where Y is the measured response obtained from each factor level combinations; β 0 is the intercept and β 1 to β 33 are the regression coefficient computed from the response Y; X 1 , X 2 , X 3 are independent factors. The contour plot for particle size and response surface plot for particle size and entrapment efficiency are found out 18,19,20 .…”

Section: Methodsmentioning

confidence: 99%

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2018

IJPSR

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For a formulation scientist, the delivery of therapeutic agents to the diseased organ has been a challenging problem. It is expected to improve the therapeutic index and reduce side effects of a drug by good delivery strategy to diseased organ. The objective of this investigation is to evaluate the targeting potential of solid lipid nanoparticle (SLN) formulation of imatinib mesylate to the lymphatic system using response surface methodology of design of experiment. Box-Behnken DOE was constructed using imatinib mesylate, compritol 888 ATO (X1) and pluronic F68 (X2) as independent factors and particle size (Y1) and entrapment efficiency (Y2) as dependant factors. The SLN formulation was prepared by hot homogenization followed by ultrasonication. Prepared SLN were analyzed by FTIR, DSC, DLS, PXRD and SEM. The optimized particle size and entrapment efficiency of the imatinib mesylate loaded solid lipid nanoparticle was found to be 190 nm and 62.5% respectively, which are sufficient to reach lymphatic system. FTIR revealed no interaction between imatinib mesylate and compritol 888 ATO. Compritol 888 ATO retained its crystalline nature in the imatinib mesylate loaded SLN formulation revealed by DSC study. The results showed that pharmacokinetic parameters such as area under the whole blood concentration-time curve, Cmax, Tmax were significantly different (P<0.05) compared with standard imatinib mesylate oral suspension and the targeting efficiency of both imatinib mesylate loaded SLN and the standard suspension at the mesenteric lymph node significantly increased (P<0.05).

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“…Based on these disease models, efforts are now being directed to develop a gene therapy approach for XLRS patients. Some studies investigated the potential of gene replacement therapy to restore retinal structure and function with knock-out mice as an XLRS animal disease model ( Zeng et al, 2004 , 2016 ; Dyka and Molday, 2007 ; Byrne et al, 2014 ; Marangoni et al, 2014 , 2017 ; Apaolaza et al, 2015 ; Ou et al, 2015 ; Ye et al, 2015 ). Traditional gene replacement therapy does have gene silence and random integration issues.…”

Section: Introductionmentioning

confidence: 99%

Recapitulating X-Linked Juvenile Retinoschisis in Mouse Model by Knock-In Patient-Specific Novel Mutation

Ding

et al. 2018

Front. Mol. Neurosci.

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X-linked juvenile retinoschisis (XLRS) is a retinal disease caused by mutations in the gene encoding retinoschisin (RS1), which leads to a significant proportion of visual impairment and blindness. To develop personalized genome editing based gene therapy, knock-in animal disease models that have the exact mutation identified in the patients is extremely crucial, and that the way which genome editing in knock-in animals could be easily transferred to the patients. Here we recruited a family diagnosed with XLRS and identified the causative mutation (RS1, p.Y65X), then a knock-in mouse model harboring this disease-causative mutation was generated via TALEN (transcription activator-like effector nucleases). We found that the b-wave amplitude of the ERG of the RS1-KI mice was significantly decreased. Moreover, we observed that the structure of retina in RS1-KI mice has become disordered, including the disarray of inner nuclear layer and outer nuclear layer, chaos of outer plexiform layer, decreased inner segments of photoreceptor and the loss of outer segments. The novel knock-in mice (RS1-KI) harboring patient-specific mutation will be valuable for development of treatment via genome editing mediated gene correction.

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Solid lipid nanoparticle-based vectors intended for the treatment of X-linked juvenile retinoschisis by gene therapy: In vivo approaches in Rs1h-deficient mouse model

Cited by 48 publications

References 36 publications

MMP-9 Downregulation with Lipid Nanoparticles for Inhibiting Corneal Neovascularization by Gene Silencing

MMP-9 Downregulation with Lipid Nanoparticles for Inhibiting Corneal Neovascularization by Gene Silencing

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Recapitulating X-Linked Juvenile Retinoschisis in Mouse Model by Knock-In Patient-Specific Novel Mutation

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