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1 General aspects (0)   1.1 Epidemiology (15)   1.2 Population genetics (0)   1.3 Pathogenesis (0)   1.4 Quality of life (19)   1.5 Glaucomas as cause of blindness (12)   1.6 Prevention and screening (11) 2 Anatomical structures in glaucoma (0)   2.1 Conjunctiva (11)   2.2 Cornea (16)   2.3 Sclera (8)   2.4 Anterior chamber angle (2)   2.5 Meshwork (0)     2.5.1 Trabecular meshwork (6)     2.5.2 Schlemms canal (3)     2.5.3 Scleral outlet channels (2)   2.6 Aqueous humor dynamics (0)     2.6.1 Production (0)     2.6.2 Outflow (0)       2.6.2.1 Trabecular meshwork (3)       2.6.2.2 Uveoscleral (0)     2.6.3 Compostion (1)   2.7 Episcleral veins and venous pressure (0)   2.8 Iris (5)   2.9 Ciliary body (3)   2.10 Lens (0)   2.11 Vitreous body (1)   2.12 Choroid, peripapillary choroid, peripapillary atrophy (9)   2.13 Retina and retinal nerve fibre layer (25)   2.14 Optic disc (26)   2.15 Optic nerve (3)   2.16 Chiasma and retrochiasmal central nervous system (6)   2.17 Stem cells (5)   2.20 Other (1) 3 Laboratory methods (0)   3.1 Microscopy (2)   3.2 Electron microscopy (0)   3.3 Immunohistochemistry (0)   3.4 Molecular genetics (0)     3.4.1 Linkage studies (0)     3.4.2 Gene studies (22)   3.5 Molecular biology incl. 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Miscellaneous (34)

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Abstract #78810 Published in IGR 20-1

Development of Targeted siRNA Nanocomplexes to Prevent Fibrosis in Experimental Glaucoma Filtration Surgery

Fernando O; Tagalakis AD; Awwad S; Brocchini S; Khaw PT; Hart SL; Yu-Wai-Man C
Molecular Therapy 2018; 26: 2812-2822

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RNAi induced by double-stranded small interfering RNA (siRNA) molecules has attracted great attention as a naturally occurring approach to silence gene expression with high specificity. The myocardin-related transcription factor/serum response factor (MRTF/SRF) pathway is a master regulator of cytoskeletal gene expression and, thus, represents a promising target to prevent fibrosis. A major hurdle to implementing siRNA therapies is the method of delivery, and we have, thus, optimized lipid-peptide-siRNA (LPR) nanoparticles containing MRTF-B siRNAs as a targeted approach to prevent conjunctival fibrosis. We tested 15 LPR nanoparticle formulations with different lipid compositions, surface charges, and targeting or non-targeting peptides in human conjunctival fibroblasts. In vitro, the LPR formulation of the DOTMA/DOPE lipid with the targeting peptide Y (LYR) was the most efficient in MRTF-B gene silencing and non-cytotoxic compared to the non-targeting formulation. In vivo, subconjunctival administration of LYR nanoparticles containing MRTF-B siRNAs doubled bleb survival in a pre-clinical rabbit model of glaucoma filtration surgery. Furthermore, MRTF-B LYR nanoparticles reduced the MRTF-B mRNA by 29.6% in rabbit conjunctival tissues, which led to significantly decreased conjunctival scarring with no adverse side effects. LYR-mediated delivery of siRNA shows promising results to increase bleb survival and to prevent conjunctival fibrosis after glaucoma filtration surgery.

National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London EC1V 2PD, UK.

Full article

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Classification:

3.5 Molecular biology incl. SiRNA (Part of: 3 Laboratory methods)
3.6 Cellular biology (Part of: 3 Laboratory methods)
12.8.10 Woundhealing antifibrosis (Part of: 12 Surgical treatment > 12.8 Filtering surgery)
2.1 Conjunctiva (Part of: 2 Anatomical structures in glaucoma)

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