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

Yuanyuan Liu, Seth D. Fortmann, Jikui Shen, Erik Wielechowski, Anna Tretiakova, Stephen Yoo, Karen Kozarsky, Jiangxia Wang, James M. Wilson, Peter A. Campochiaro

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


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. Wet age-related macular degeneration (AMD) is treated by repeated injections of VEGF-neutralizing proteins. Subretinal injection of AAV8-antiVEGFfab provides sustained expression of an anti-VEGF antibody fragment that suppresses neovascularization and vascular leakage in wet AMD mouse models, enabling clinical trials that could provide new treatment paradigms for chronic retinal/choroidal vascular diseases.

Original languageEnglish (US)
Pages (from-to)542-549
Number of pages8
JournalMolecular Therapy
Issue number2
StatePublished - Feb 7 2018


  • choroidal neovascularization
  • gene therapy
  • retinal vascular diseases
  • subretinal injections
  • viral vector

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery


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