AAV8-antiVEGFfab Ocular Gene Transfer for Neovascular Age-Related Macular Degeneration.

Abstract

Sustained suppression of VEGF is needed in many patients with neovascular age-related macular degeneration (NVAMD), and gene transfer of a VEGF-neutralizing protein is a promising approach to achieve it. Initial clinical trials testing this approach have shown encouraging signals, but evidence of robust transgene expression and consistent antiangiogenic and antipermeability activity has been lacking. In this study, we demonstrate expression of an anti-human VEGF antibody fragment (antiVEGFfab) after subretinal injection of AAV8-antiVEGFfab. In transgenic mice expressing human VEGF in retina (rho/VEGF mice), a model of type 3 choroidal neovascularization (NV), eyes injected with ≥1 × 107 gene copies (GC) of AAV8-antiVEGFfab had significantly less mean area of NV than null vector-injected eyes. A dose-dependent response was observed with modest reduction of NV with ≤3 × 107, >50% reduction with ≥1 × 108 GC and almost complete elimination of NV with 3 × 109 or 1 × 1010 GC. In Tet/opsin/VEGF mice, in which doxycycline-induced high expression of VEGF leads to severe vascular leakage and exudative retinal detachment (RD), reduction of total RD by 70%-80% occurred with 3 × 109 or 1 × 1010 GC of AAV8-antiVEGFfab, an effect that was sustained for at least a month. These data strongly support initiating clinical trials testing subretinal injection of AAV8-antiVEGFfab in patients with NVAMD.

• Authors: Yuanyuan Liu, Seth D Fortmann, Jikui Shen, Erik Wielechowski, Anna Tretiakova, Stephen Yoo, Karen Kozarsky, Jiangxia Wang, James M Wilson, Peter A Campochiaro
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 26 Issue 2 Pg. 542-549 (02 07 2018) ISSN: 1525-0024 [Electronic] United States
• PMID: 29292162 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Chemical References

• Immunoglobulin Fab Fragments
• Vascular Endothelial Growth Factor A

Topics

• Animals
• Choroidal Neovascularization (genetics, pathology, therapy)
• Dependovirus (genetics)
• Disease Models, Animal
• Gene Expression
• Gene Order
• Gene Transfer Techniques
• Genetic Therapy
• Genetic Vectors (administration & dosage, genetics)
• Immunoglobulin Fab Fragments (genetics, metabolism)
• Macular Degeneration (genetics, pathology, therapy)
• Mice
• Retinal Neovascularization (genetics, pathology, therapy)
• Transduction, Genetic
• Transgenes
• Vascular Endothelial Growth Factor A (antagonists & inhibitors)