Corneal chemical burn treatment through a delivery system consisting of TGF-β1 siRNA: in vitro and in vivo

Abstract

Chemical burns are major causes of corneal blindness. Transforming growth factor beta-1 (TGFβ) plays an important role in induction of corneal inflammation-related-fibrosis leading to the blindness. Here, a topical delivery system consisting anti-fibrotic TGF-β siRNA, an inflammatory suppressing gene, was designed for treatment of corneal injuries. TGF-β siRNA loaded in nanoparticles (NPs) made up of polyethyleneimine polymer demonstrated high fibroblast transfection efficiency. Moreover, TGF-β and PDGF genes and ECM deposition were suppressed in isolated human corneal fibroblasts. NPs inhibited proliferation and transformation of fibroblasts to myofibroblasts by S-phase arrest and α-SMA suppression in vitro, respectively. The mentioned finding was also confirmed in vivo, addressing high wound-healing potential of prepared gene delivery system which was superior to conventional betamethasone treatment. Besides, CD4 and α-SMA antibody staining showed inhibited angiogenesis and myofibroblast accumulation in treated corneas. This study opens a new way for treating corneal fibrosis through topical siRNA delivery.

Challenges and strategies for the delivery of biologics to the cornea

“…Complexing siRNA with PEI led to an improved internalization into the fibroblasts that migrate to the epithelium after corneal wounding. However, a slight inflammatory response in the treated group was observed, which was most likely attributed to PEI [66]. As PEI is generally considered as a toxic polymer, mainly due to its strong cationic charge density, it might not be an optimal excipient for ocular delivery of nucleic acids [68].…”

“…To improve corneal wound healing, Zahir-Jouzdani et al explored polyethylenimine (PEI) to deliver siRNA targeting TGF-β1 [66]. PEI is a positively charged polymer that is commonly used to form complexes with negatively charged nucleic acids [67].…”

Topical Pirfenidone-Loaded Liposomes Ophthalmic Formulation Reduces Haze Development after Corneal Alkali Burn in Mice

“…Corneal healing following alkali burns rarely restores the transparency and Pharmaceutics 2022, 14, 316 2 of 15 culminates in corneal haze and opacity [1][2][3]5,6]. Corneal myofibroblasts, α-smooth muscle actin (αSMA)-positive cells, are the main cells involved in corneal haze development [7] and are generated from corneal keratocytes through a transforming growth factor β (TGFβ)-mediated epithelial-mesenchymal transition process, triggering αSMA expression and increasing collagen I secretion [8,9].…”

Genetic Screening Revealed Latent Keratoconus in Asymptomatic Individuals

“…The second candidate KC gene is the TGFBI (OMIM 601692) gene, which is responsible for Fuchs endothelial corneal dystrophy. TGFβ1 is reported to be involved in corneal scar formation and fibrosis (Zahir-Jouzdani et al, 2018), and recently, a study found that downregulation of the core elements of the TGF-β pathway influences corneal organization in KC cornea (Kabza et al, 2017). Recently, several mutations in TGFBI were identified in Chinese and Polish KC patients, indicating a potential role of TGFBI gene in KC pathogenesis (Guan et al, 2012;Bykhovskaya et al, 2016;Karolak et al, 2016).…”