Novel subthreshold retinal laser treatment with ERG-based thermal dosimetry activates hormetic heat response in pig RPE in vivo

Boosting natural mechanisms to retain cellular homeostasis and combat oxidative stress by inducing a hormetic heat shock to retinal pigment epithelium with non-damaging transpupillary laser heating, i.e., with subthreshold laser treatment (SLT), has been suggested as a promising therapeutic target for many retinal diseases, including age-related macular degeneration. However, the therapeutic temperature window for the treatments is narrow and thermal dosimetry is unavailable. Here we introduce an SLT modality where the retinal temperature is monitored with electroretinography (ERG)-based thermal dosimetry and demonstrate its feasibility with anesthetized pigs. In 60-second treatments with 810 nm laser, the ED50 peak temperature for visible lesion generation was 48{degrees}C and the relative temperature determination error was below 10% from the temperature increase. Heat shock protein expression increased, and autophagy was activated at 44.2 {degrees}C and no signs of oxidative stress or apoptosis emerged at 44.2 {degrees}C or 46.5 {degrees}C. The demonstrated method permits a controlled activation of intracellular chaperones and waste clearance in RPE cell with a clear temperature margin for adverse events. In the clinical setting, ERG-based dosimetry would allow safe and personalized SLTs for retinal diseases currently lacking effective treatments.