UMMS Affiliation

Department of Ophthalmology and Visual Sciences; Horae Gene Therapy Center; Viral Vector Core; Department of Microbiology and Physiological Systems; Li Weibo Institute for Rare Diseases Research

Publication Date


Document Type



Eye Diseases | Genetics and Genomics | Ophthalmology | Therapeutics


The wet form of age-related macular degeneration is characterized by neovascular pathologies that, if untreated, can result in edemas followed by rapid vision loss. Inhibition of vascular endothelial growth factor (VEGF) has been used to successfully treat neovascular pathologies of the eye. Nonetheless, some patients require frequent intravitreal injections of anti-VEGF drugs, increasing the burden and risk of complications from the procedure to affected individuals. Recombinant adeno-associated virus (rAAV)-mediated expression of anti-VEGF proteins is an attractive alternative to reduce risk and burden to patients. However, controversy remains as to the safety of prolonged VEGF inhibition in the eye. Here, we show that two out of four rAAV serotypes tested by intravitreal delivery to express the anti-VEGF drug conbercept lead to a dose-dependent vascular sheathing pathology that is characterized by immune cell infiltrates, reminiscent of vasculitis in humans. We show that this pathology is accompanied by increased expression in vascular cell adhesion molecule 1 (VCAM1) and intercellular adhesion molecule 1 (ICAM1), both of which promote extravasation of immune cells from the vasculature. While formation of the vascular sheathing pathology is prevented in immunodeficient Rag-1 mice that lack B and T cells, increased expression of VACM1 and ICAM1 still occurs, indicating that inhibition of VEGF function leads to expression changes in cell adhesion molecules that promote extravasation of immune cells. Importantly, a 10-fold lower dose of one of the vectors that cause a vascular sheathing pathology is still able to reduce edemas resulting from choroidal neovascularization without causing any vascular sheathing pathology and only a minimal increase in VCAM1 expression. The data suggest that treatments of neovascular eye pathologies with rAAV-mediated expression of anti VEGF drugs can be developed safely. However, viral load needs to be adjusted to the tropisms of the serotype and the expression pattern of the promoter.


AMD, CNV, DR, VEGF, anti-VEGF, conbercept, rAAV, vasculitis, wet AMD

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Copyright Shun-Yun Cheng et al., 2021; Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the Creative Commons License [CC-BY] (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

DOI of Published Version



Cheng SY, Luo Y, Malachi A, Ko J, Su Q, Xie J, Tian B, Lin H, Ke X, Zheng Q, Tai PWL, Gao G, Punzo C. Low-Dose Recombinant Adeno-Associated Virus-Mediated Inhibition of Vascular Endothelial Growth Factor Can Treat Neovascular Pathologies Without Inducing Retinal Vasculitis. Hum Gene Ther. 2021 Jul;32(13-14):649-666. doi: 10.1089/hum.2021.132. PMID: 34182803; PMCID: PMC8312021. Link to article on publisher's site

Journal/Book/Conference Title

Human gene therapy

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Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.