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Stable inhibition of choroidal neovascularization by adeno-associated virus 2/8-vectored bispecific molecules

Gene Therapy volume 31, pages 511–523 (2024)Cite this article

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Abstract

Neovascular age-related macular degeneration (nAMD) causes severe visual impairment. Pigment epithelium-derived factor (PEDF), soluble CD59 (sCD59), and soluble fms-like tyrosine kinase-1 (sFLT-1) are potential therapeutic agents for nAMD, which target angiogenesis and the complement system. Using the AAV2/8 vector, two bi-target gene therapy agents, AAV2/8-PEDF-P2A-sCD59 and AAV2/8-sFLT-1-P2A-sCD59, were generated, and their therapeutic efficacy was investigated in laser-induced choroidal neovascularization (CNV) and Vldlr−/− mouse models. After a single injection, AAV2/8-mediated gene expression was maintained at high levels in the retina for two months. Both AAV2/8-PEDF-P2A-sCD59 and AAV2/8-sFLT-1-P2A-sCD59 significantly reduced CNV development for an extended period without side effects and provided efficacy similar to two injections of current anti-vascular endothelial growth factor monotherapy. Mechanistically, these agents suppressed the extracellular signal-regulated kinase and nuclear factor-κB pathways, resulting in anti-angiogenic activity. This study demonstrated the safety and long-lasting effects of AAV2/8-PEDF-P2A-sCD59 and AAV2/8-sFLT-1-P2A-sCD59 in CNV treatment, providing a promising therapeutic strategy for nAMD.

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Fig. 1: The efficiency of intravitreal AAV2/8-mediated gene delivery in vitro and in vivo.
Fig. 2: Treatment with AAV2/8-mediated genes via intravitreal delivery effectively inhibited laser‑induced CNV.
Fig. 3: AAV2/8-mediated gene therapy resulted in long-term inhibition of laser‑induced CNV.
Fig. 4: Intravitreal delivery of AAV2/8‑mediated genes attenuated retinal neovascularization in a Vldlr−/− mouse model.
Fig. 5: Extracellular signal-regulated kinase and nuclear factor-κB pathway activation were downregulated by AAV2/8‑mediated gene therapy.
Fig. 6: Safety of AAV2/8‑mediated gene delivery into the eye.

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Funding

Funding

This work was supported by the National Key Research and Development Program of China (2021YFC2401404) and the National Natural Science Foundation of China (82020108007, 82330031, 32070926, 82122018).

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  1. These authors contributed equally: Tinghui Bai, Bohao Cui

Authors and Affiliations

  1. Department of Ophthalmology, Tianjin Medical University General Hospital, Ministry of Education International Joint Laboratory of Ocular Diseases, Tianjin Key Laboratory of Ocular Trauma, Tianjin Institute of Eye Health and Eye Diseases, China-UK “Belt and Road” Ophthalmology Joint Laboratory, Tianjin, China

    Tinghui Bai, Bohao Cui, Siyue Chen, Yanfang Zhu, Dongxue Lin, Mei Du, Xiaohong Wang & Hua Yan

  2. Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China

    Man Xing, Yingying Guo & Dongming Zhou

  3. Department of Pharmacology, Tianjin Key Laboratory of Inflammation Biology, the Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China

    Mei Du & Xiaohong Wang

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Contributions

DZ and HY conceived the project, designed the study, and acquired funding. DZ, HY, XW supervised the study. TB, SC, YZ, DL, MX, YG, MD performed the research and analyzed the data. TB, BC, DZ, XW, and HY wrote the manuscript. All the authors reviewed the paper and approved the final draft of the manuscript.

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Correspondence to Xiaohong Wang, Dongming Zhou or Hua Yan.

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No human samples were used in the study. The animal experiments were approved by the Institutional Animal Care and Use Committee of Tianjin Medical University (TMUaMEC 2022006).

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Bai, T., Cui, B., Xing, M. et al. Stable inhibition of choroidal neovascularization by adeno-associated virus 2/8-vectored bispecific molecules. Gene Ther 31, 511–523 (2024). https://doi.org/10.1038/s41434-024-00461-1

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