Development of targeted siRNA nanocomplexes to prevent fibrosis in experimental glaucoma filtration surgery

Fernando, Owen, Tagalakis, Aristides, Awwad, Sahar, Brocchini, Steve, Khaw, Peng T., Hart, Stephen L. and Yu-Wai-Man, Cynthia (2018) Development of targeted siRNA nanocomplexes to prevent fibrosis in experimental glaucoma filtration surgery. Molecular Therapy. ISSN 1525-0016 DOI https://doi.org/10.1016/j.ymthe.2018.09.004

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Abstract

RNA interference 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 optimised lipid-peptide-siRNA (LPR) nanoparticles containing MRTF-B siRNAs as a targeted approach to prevent conjunctival fibrosis. We tested fifteen 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 DOTMA/DOPE lipid with the targeting peptide Y (LYR) was the most efficient in MRTF-B gene silencing and noncytotoxic 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.

Item Type: Article
Uncontrolled Keywords: Nanoparticle, siRNA, targeting peptide, glaucoma, fibrosis
Subjects: Q Science > QH Natural history > QH301 Biology
Q Science > QH Natural history > QH426 Genetics
Divisions: Biology
Date Deposited: 27 Sep 2018 09:06
URI: http://repository.edgehill.ac.uk/id/eprint/10655

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