Table 1.
Preclinical studies with Gene transfer and non-gene transfer techniques targeting TGFβ/Smad in ocular fibrosis.
| Target | Treatment Strategy | In Vitro and In Vivo Models | References |
|---|---|---|---|
| Gene transfer techniques | |||
| TGFβ | Adenoviral gene transfer of soluble human type II TGFβ receptor | In vitro in COS cells, in vivo in mouse alkali-burned cornea. | Sakamoto et al., Gene Ther. 2000 |
| TGFβ | siRNAs transfection of type II TGFβ receptor | In vitro in cultured human corneal fibroblasts. In vivo in mouse model of ocular inflammation and fibrosis. | Nakamura et al., Mol Vis. 2004 |
| Smad3 | Knocking out of Smad3 by gene targeting | In vivo in mouse alkali-burned cornea. | Saika et al., Am. J. Pathol. 2005b |
| Smad7 | Adenoviral gene transfer of Smad7 | In vivo in mouse alkali-burned cornea. | Saika et al., Am. J. Pathol. 2005b |
| In vitro in cultured human subconjunctival fibroblasts, in vivo in mouse injury-induced wound healing of conjunctiva. | Yamanaka et al., Mol Vis. 2006 | ||
| In vivo in mouse injured lens epithelium. | Saika et al., Lab Invest. 2004 | ||
| In vitro in ARPE-19 human RPE cells, in vivo PVR mouse model. | Saika et al., Arch Ophthalmol. 2007 | ||
| BMP-7 | Adenoviral gene transfer of BMP-7 |
In vivo in mouse alkali-burned cornea.
In vitro in human corneal fibroblasts and myofibroblasts, in vivo in rabbit model of corneal fibrosis. |
Saika et al., Lab Invest. 2005
Gupta et al., Invest Ophthalmol Vis Sci. 2018 |
| BMP-7 Id2 Id3 |
Adenoviral gene transfer of BMP-7, Id2, or Id3 |
In vivo in mouse injured lens epithelium. | Saika et al., Am J Physiol Cell Physiol. 2006 |
| PPARγ | Adenoviral gene transfer of PPARγ | In vitro in mouse ocular fibroblasts and macrophages, and in human corneal epithelial cell line, in vivo in mouse alkali-burned cornea. | Saika et al., Am J Physiol Cell Physiol. 2007 |
| Decorin | Mammalian vector gene transfer of Decorin Adenoviral gene transfer of Decorin Adenoviral gene transfer of Decorin |
In vitro in human corneal fibroblasts.
In vivo rabbit model of corneal fibrosis. In vivo rabbit model of corneal fibrosis. |
Mohan et al., Exp Eye Res. 2010
Mohan et al., Invest Ophthalmol Vis Sci. 2011 Mohan et al., PLoS One. 2011 |
| Nox4 | Adenoviral gene transfer of Ad-Nox4i | In vitro in HTFs, in vivo in mouse model of GFS. | Shah et al., Antioxidants (Basel). 2020 |
| p38MAPK | Adenoviral gene transfer of DN p38MAPK | In vivo in a mouse model of PVR. | Saika et al., Lab Invest. 2005 |
| Non-gene transfer techniques | |||
| SN50 | Inhibition of NF-κB | In vivo in mouse alkali-burned cornea. | Saika et al., Am. J. Pathol. 2005c |
| Disulfiram | Inhibition of ALDH | In vitro in human OMMP fibroblasts, in vivo in mouse model of scarring AED. | Ahadome et al., JCI Insight 2016 |
| Halofuginone | Up-regulation of Smad7 and down-regulation of TβR-II | In vitro in human corneal fibroblasts. | Nelson et al., Mol Vis. 2012 |
| Genipin | Inhibition of Smad2, p38 MAPK and CTGF | In vitro in lens epithelial cell line alpha-TN4. | Kitano et al., J Cataract Refract Surg. 2006 |
| Emodin | Inhibition of TNFα | In vitro in human subconjunctival fibroblasts, in vivo in mouse alkali-burned cornea. | Kitano et al., Invest Ophthalmol Vis Sci. 2007 |
| Tetrandrine | Upregulation of Smad7 and downregulation of Smad2 | In vitro in human subconjunctival fibroblasts. | Kitano et al., Curr Eye Res. 2008 |
| Pirfenidone | Inhibition of TGF-β1, β2, and β3 | In vitro in human ocular fibroblasts. | Stahnke et al., PLoS One. 2017 |
| CTGF | Inhibition of CTGF | In vivo in a rabbit model of GFS. | Wang et al., Int. J. Ophthalmol. 2011 |
| AMA0526 Y-27632 NSC23766 |
Inhibition of Rho-kinase |
In vivo in a rabbit model of GFS.
In vitro in HTFs, in vivo in a rabbit model of GFS. In vitro in ARPE-19 human RPE cells. In vitro in HTFs. |
Van de Velde et al., Prog Brain Res. 2015
Honjo et al., Invest Ophthalmol Vis Sci. 2007 Zhu et al., Int J Ophthalmol. 2013 Tovell et al., Invest Ophthalmol Vis Sci. 2012 |
| Sulforaphane LiCl 3-MA |
Inhibition of PI3K/Akt |
In vitro in human conjunctival fibroblasts.
In vitro in HTFs. In vivo in mouse model of subretinal fibrosis. |
Liu et al., Int J Ophthalmol. 2020
Chung et al., Biotechnol Lett. 2014 Bo et al., J Ocul Pharmacol Ther. 2020 |
| SB203580 SB202190 |
Inhibition of p38MAPK |
In vitro in HTFs.
In vitro in ARPE-19 human RPE cells. |
Meyer-Ter-Vehn et al., Invest Ophthalmol Vis Sci. 2006
Saika et al., Lab Invest. 2005 |
| RO4929097 LY411575 DAPT |
Inhibition of Notch |
In vitro in human MIO-M1 Müller cells, in vivo in a murine model of retinal fibrosis.
In vitro in RPE cells, in vivo in mouse model of PVR. In vitro in ARPE-19 human RPE cells. |
Fan et al., Theranostics. 2020
Zhang et al., Histochem Cell Biol. 2017 Chen et al. Curr Mol Med. 2014 |
TGFβ, transforming growth factor β; siRNAs, small interference RNAs; Smad, small mothers against decapentaplegic; RPE, retinal pigment epithelium; PVR, proliferative vitreoretinopathy; BMP-7, bone morphogenic protein-7; Id2 and Id3, inhibitors of differentiation 2 and 3; PPARγ, peroxisome proliferator-activated receptor γ; Nox4, NADPH oxidase 4; Ad-Nox4i, Nox4 small interfering RNA (siRNA); p38 MAPK, p38 mitogen-activated protein kinase; DN, dominant-negative; NF-κB, nuclear factor-κB; ALDH, aldehyde dehydrogenase; OMMP, ocular mucous membrane pemphigoid; AED, allergic eye disease; TβR-II, TGF-β receptor type II; TNFα, tumor necrosis factor α; CTGF, connective tissue growth factor; HTFs, human Tenon’s fibroblasts; GFS, glaucoma filtration surgery; PI3K/Akt, phosphatidylinositol-3-kinase/Akt; LiCl, lithium chloride; 3-MA, 3-methyladenine.