Incorporating Differential Gene Expression Analysis with Predictive Biomarkers to Identify Novel Therapeutic Drugs for Fuchs Endothelial Corneal Dystrophy

Huaming Wen; Ryan A Gallo; Xiaosheng Huang; Jiamin Cai; Shaoyi Mei; Ammad Ahmad Farooqi; Jun Zhao; Wensi Tao

doi:10.1155/2021/5580595

Incorporating Differential Gene Expression Analysis with Predictive Biomarkers to Identify Novel Therapeutic Drugs for Fuchs Endothelial Corneal Dystrophy

J Ophthalmol. 2021 Jun 28:2021:5580595. doi: 10.1155/2021/5580595. eCollection 2021.

Authors

Huaming Wen^{1

2}, Ryan A Gallo³, Xiaosheng Huang^{4

5}, Jiamin Cai⁴, Shaoyi Mei⁵, Ammad Ahmad Farooqi⁶, Jun Zhao^{1

5}, Wensi Tao^{3

7}

Affiliations

¹ Department of Ophthalmology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong, China.
² Department of Ophthalmology, Baoan Central Hospital of Shenzhen, The Fifth Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong 518102, China.
³ Dr. Nasser Al-Rashid Orbital Vision Research Center, Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL, USA.
⁴ School of Ophthalmology & Optometry Affiliated to Shenzhen University, Shenzhen Eye Hospital, Shenzhen 518040, Guangdong, China.
⁵ Shenzhen Eye Hospital Affiliated to Jinan University, Shenzhen Eye Institute, Shenzhen 518040, Guangdong, China.
⁶ Institute of Biomedical and Genetic Engineering (IBGE), Islamabad 44000, Pakistan.
⁷ Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, FL, USA.

Abstract

Purpose: Based on the differential gene expression analysis for predictive biomarkers with RNA-Sequencing data from Fuchs endothelial corneal dystrophy (FECD) patients, we are aiming to evaluate the efficacy of Library of Integrated Network-based Cellular Signatures (LINCS) perturbagen prediction software to identify novel pharmacotherapeutic targets that can revert the pathogenic gene expression signatures and reverse disease phenotype in FECD.

Methods: A publicly available RNA-seq dataset was used to compare corneal endothelial specimens from controls and patients with FECD. Based on the differential gene expression analysis for predictive biomarkers, we evaluated the efficacy of LINCS perturbagen prediction software to identify novel therapeutic targets that can revert the pathogenic gene expression signatures and reverse disease phenotypes in FECD.

Results: The RNA-seq dataset of the corneal endothelial cells from FECD patients revealed the differential gene expression signatures of FECD. Many of the differential expressed genes are related to canonical pathways of the FECD pathogenesis, such as extracellular matrix reorganization and immunological response. The expression levels of genes VSIG2, IL18, and ITGB8 were significantly increased in FECD compared with control. Meanwhile, the expression levels of CNGA3, SMOX, and CERS1 were significantly lower in the FECD than in control. We employed LINCS L1000 Characteristic Direction Signature Search Engine (L1000-CDS2) to investigate pathway-based molecular treatment. L1000-CDS2 predicted that small molecule drugs such as histone deacetylase (HDAC) inhibitors might be a potential candidate to reverse the pathological gene expression signature in FECD.

Conclusions: Based on differential gene expression signatures, several candidate drugs have been identified to reverse the disease phenotypes in FECD. Gene expression signature with LINCS small molecule prediction software can discover novel preclinical drug candidates for FECD.