Targeting FSCN1 with an oral small-molecule inhibitor for treating ocular neovascularization

Wen Bai; Jun-Song Ren; Min Xia; Ya Zhao; Jing-Juan Ding; Xi Chen; Qin Jiang

doi:10.1186/s12967-023-04225-0

Targeting FSCN1 with an oral small-molecule inhibitor for treating ocular neovascularization

J Transl Med. 2023 Aug 18;21(1):555. doi: 10.1186/s12967-023-04225-0.

Authors

Wen Bai^#^{1

2}, Jun-Song Ren^#^{1

2}, Min Xia^#^{1

2}, Ya Zhao^{1

2}, Jing-Juan Ding^{1

2}, Xi Chen^{1

2

3}, Qin Jiang^{4

5}

Affiliations

¹ The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China.
² The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, China.
³ Department of Ophthalmology, Northern Jiangsu People's Hospital, Yangzhou, China.
⁴ The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China. jqin710@vip.sina.com.
⁵ The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, China. jqin710@vip.sina.com.

^# Contributed equally.

Abstract

Background: Ocular neovascularization is a leading cause of blindness and visual impairment. While intravitreal anti-VEGF agents can be effective, they do have several drawbacks, such as endophthalmitis and drug resistance. Additional studies are necessary to explore alternative therapeutic targets.

Methods: Bioinformatics analysis and quantitative RT-PCR were used to detect and verify the FSCN1 expression levels in oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV) mice model. Transwell, wound scratching, tube formation, three-dimensional bead sprouting assay, rhodamine-phalloidin staining, Isolectin B4 staining and immunofluorescent staining were conducted to detect the role of FSCN1 and its oral inhibitor NP-G2-044 in vivo and vitro. HPLC-MS/MS analysis, cell apoptosis assay, MTT assay, H&E and tunnel staining, visual electrophysiology testing, visual cliff test and light/dark transition test were conducted to assess the pharmacokinetic and security of NP-G2-044 in vivo and vitro. Co-Immunoprecipitation, qRT-PCR and western blot were conducted to reveal the mechanism of FSCN1 and NP-G2-044 mediated pathological ocular neovascularization.

Results: We discovered that Fascin homologue 1 (FSCN1) is vital for angiogenesis both in vitro and in vivo, and that it is highly expressed in oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV). We found that NP-G2-044, a small-molecule inhibitor of FSCN1 with oral activity, can impede the sprouting, migration, and filopodia formation of cultured endothelial cells. Oral NP-G2-044 can effectively and safely curb the development of OIR and CNV, and increase efficacy while overcoming anti-VEGF resistance in combination with intravitreal aflibercept (Eylea) injection.

Conclusion: Collectively, FSCN1 inhibition could serve as a promising therapeutic approach to block ocular neovascularization.

Keywords: Angiogenesis; FSCN1; NP-G2-044; Ocular pathologies; Vascular tip cell.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis
Choroidal Neovascularization* / drug therapy
Endothelial Cells
Mice
Retinal Diseases*
Tandem Mass Spectrometry

Substances

FSCN1 protein, human