Stable inhibition of choroidal neovascularization by adeno-associated virus 2/8-vectored bispecific molecules.
Tinghui BaiBohao CuiMan XingSiyue ChenYanfang ZhuDongxue LinYingying GuoMei DuXiaohong WangDongming ZhouHua YanPublished in: Gene therapy (2024)
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.
Keyphrases
- gene therapy
- vascular endothelial growth factor
- tyrosine kinase
- age related macular degeneration
- gene expression
- nuclear factor
- epidermal growth factor receptor
- endothelial cells
- toll like receptor
- optical coherence tomography
- diabetic retinopathy
- mouse model
- immune response
- clinical trial
- dna methylation
- randomized controlled trial
- single molecule
- drug induced
- study protocol
- double blind