AAV-NRF2 protects retinal and choroidal vasculature in a GDF15-dependent manner in an oxidative damage model of AMD

Oxidative stress is proposed to be a driver of age-related diseases. Age-related macular degeneration (AMD) is one such disease, where the retinal pigment epithelium (RPE) is affected early in the disease. Vasculature damage also occurs, sometimes preceding RPE damage. To model some aspects of dry AMD, we used the NaIO₃ mouse model of oxidative damage. Disruption of the deep retinal vascular plexus, disorganization and death of capillaries within the choriocapillaris, and marked electroretinographic decline were observed. Adeno-associated virus (AAV) overexpressing the transcription factor, NRF2, which induces antioxidation enzymes and represses inflammation, was tested for protection of damage. The BEST1 promoter limited expression to the RPE. The RPE, photoreceptors, and vascular architecture in both retinal and choroidal compartments were protected. Conditioned medium from RPE-choroid explants, infected by AAV8/BEST1-NRF2, was sufficient to transfer partial protection in vivo, suggesting that NRF2 induces a protective secreted factor(s). Analysis of RNA-seq data nominated growth differentiation factor 15 (GDF15) as a candidate secreted mediator. Injection of recombinant GDF15 reproduced key protective phenotypes in vivo, whereas Gdf15 deficiency attenuated NRF2-mediated rescue. Pharmacologic inhibition of TGF-β receptor signaling diminished NRF2-induced protection, supporting involvement of this signaling pathway. In a laser-induced choroidal neovascularization model, intravitreal GDF15 injection reduced fluorescein leakage and lesion size. These findings support a model in which NRF2 activation in the RPE induces expression of GDF15, which is capable of protecting the RPE, photoreceptors, and the retinal and choroidal vasculature. NRF2 and GDF15 have therapeutic potential for ocular diseases, as well as for other diseases with vascular pathology.