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

Owen Fernando, Aristides Tagalakis, Sahar Awwad, Steve Brocchini, Peng T. Khaw, Stephen L. Hart, Cynthia Yu-Wai-Man

Research output: Contribution to journalArticle

9 Citations (Scopus)
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Abstract

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. RNAi induced by double-stranded, small interfering RNA (siRNA) is a naturally occurring approach to silence gene expression with high specificity. Yu-Wai-Man and colleagues show that lipid-peptide-siRNA (LPR) nanoparticles significantly increase bleb survival and prevent conjunctival fibrosis in a pre-clinical model of glaucoma filtration surgery.

Original languageEnglish
Pages (from-to)2812-2822
Number of pages11
JournalMolecular Therapy
Volume26
Issue number12
Early online date11 Sep 2018
DOIs
Publication statusPublished - 5 Dec 2018

Keywords

  • Nanoparticle
  • siRNA
  • targeting peptide
  • glaucoma
  • fibrosis
  • nanoparticle

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