Retinal Organoid-Derived Exosomes Reduce CNV Lesion and Restore RPE Integrity in Mouse Laser-Induced Choroidal...

Area of Science:

• Ophthalmology
• Regenerative Medicine
• Cell Biology

Background:

• Neovascular age-related macular degeneration (nAMD) poses a significant challenge due to limitations of current anti-VEGF monotherapies.
• Developing novel therapeutic strategies is crucial for improving nAMD treatment outcomes.

Purpose of the Study:

• To investigate the therapeutic potential of exosomes derived from human induced pluripotent stem cell (hiPSC)-derived retinal organoids (RO-Exo) for nAMD.
• To compare the efficacy of RO-Exo with aflibercept, a standard anti-VEGF treatment, in a mouse model of choroidal neovascularization (CNV).

Main Methods:

• RO-Exo were isolated from hiPSC-derived retinal organoids and administered via intravitreal injection in a laser-induced CNV mouse model.
• Therapeutic effects were assessed by measuring vascular leakage, CNV size, gene/protein expression (HIF-1α, VEGF-A, fibronectin), Retinal Pigment Epithelium (RPE) integrity, and MAPK pathway activation.

Main Results:

• Intravitreal injection of RO-Exo led to significant retinotropic distribution.
• RO-Exo markedly reduced vascular leakage and CNV size, outperforming aflibercept in suppressing HIF-1α and VEGF-A.
• RO-Exo demonstrated anti-fibrotic effects by downregulating fibronectin and restored RPE integrity, while also inhibiting MAPK pathway activation.

Conclusions:

• RO-Exo possess multi-target therapeutic properties, including anti-angiogenic, anti-fibrotic, and neuroprotective actions.
• RO-Exo represent a promising alternative therapeutic agent for nAMD, potentially overcoming the limitations of current anti-VEGF therapies.