Chimpanzee adenovirus-mediated multiple gene therapy for age-related macular degeneration

Selena Wei-Zhang; Bohao Cui; Man Xing; Jiaojiao Liu; Yingying Guo; Kai He; Tinghui Bai; Xue Dong; Yi Lei; Wei Zhou; Hui Zhou; Shengnan Liu; Xiaohong Wang; Dongming Zhou; Hua Yan

doi:10.1016/j.isci.2023.107939

Chimpanzee adenovirus-mediated multiple gene therapy for age-related macular degeneration

iScience. 2023 Sep 16;26(10):107939. doi: 10.1016/j.isci.2023.107939. eCollection 2023 Oct 20.

Authors

Selena Wei-Zhang^{1

2

3}, Bohao Cui^{1

2}, Man Xing³, Jiaojiao Liu³, Yingying Guo³, Kai He^{1

2}, Tinghui Bai^{1

2

3}, Xue Dong^{1

2}, Yi Lei^{1

2}, Wei Zhou¹, Hui Zhou¹, Shengnan Liu¹, Xiaohong Wang^{1

2

4}, Dongming Zhou³, Hua Yan^{1

2

5}

Affiliations

¹ Department of Ophthalmology, Tianjin Key Laboratory of Ocular Trauma, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, China.
² Laboratory of Molecular Ophthalmology, Tianjin Medical University, Tianjin 300070, China.
³ Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
⁴ Department of Pharmacology, Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
⁵ School of Medicine, Nankai University, Tianjin, China.

Abstract

Neovascular age-related macular degeneration AMD (nAMD) is characterized by choroidal neovascularization (CNV) and could lead to irreversible blindness. However, anti-vascular endothelial growth factor (VEGF) therapy has limited efficacy. Therefore, we generated a chimpanzee adenoviral vector (AdC68-PFC) containing three genes, pigment endothelial-derived factor (PEDF), soluble fms-like tyrosine kinase-1 (sFlt-1), and soluble forms of CD59 (sCD59), to treat nAMD. The results showed that AdC68-PFC mediated a strong onset of PEDF, sFlt-1, and sCD59 expression both in vivo and in vitro. AdC68-PFC showed preventive and therapeutic effects following intravitreal (IVT) injection in the laser-induced CNV model and very low-density lipoprotein receptor-deficient (Vldlr^-/-) mouse model. In vitro assessment indicated that AdC68-PFC had a strong inhibitory effect on endothelial cells. Importantly, the safety test showed no evidence of in vivo toxicity of adenovirus in murine eyes. Our findings suggest that AdC68-PFC may be a long-acting and safe gene therapy vector for future nAMD treatments.

Keywords: Genetic engineering; Model organism; Ophthalmology; Techniques in genetics.