Retinal organoid model advances understanding of dry age-related macular degeneration

Age-related macular degeneration (AMD), classified into dry and wet types, poses a significant threat to the vision of the elderly population globally. Despite its prevalence, the exact molecular mechanisms underlying the damage to retinal pigment epithelial cells (RPEs) and photoreceptor cells (PCs) in dry AMD remain poorly understood. Hence, there is a critical need for the development of human retinal models that can mimic dry AMD.

This research, published in the Genes & Diseases journal by a team from The Third Medical Center of Chinese PLA General Hospital, Medical School of the Chinese PLA General Hospital, and Chinese Academy of Medical Sciences & Peking Union Medical College, utilized human retinal organoids (ROs) stimulated with sodium iodate to establish a dry AMD model.

Building on their earlier work, which demonstrated the presence of abundant RPEs and PCs in ROs after 186 days of differentiation, the researchers developed a human retinal degeneration model (hRO-AMD) by adding sodium iodate to the culture environment, which simulated the key pathological processes of human dry AMD.

Subsequently, the team identified two compounds—metformin, a widely used anti-diabetic drug, and TN1, a fetal hemoglobin (HbF) inducer—as having protective effects against retinal degeneration. Interestingly, both metformin and TN1 significantly reduced sodium iodate-induced apoptosis in ROs, decreased oxidative stress in photoreceptors and alleviated RPE cell damage, thus providing a protective effect on the retina.

Further RNA-seq analysis revealed that both metformin and TN1 exerted their protective effects through upregulation of the HMOX1 gene, which is involved in resistance to oxidative stress. Taken together, these findings suggest that HMOX1 may be an important molecule mediating the protective effects of metformin and TN1 against oxidative stress-induced injury.

The researchers acknowledge that the current model does not yet fully simulate all aspects of dry AMD pathogenesis, such as vascular and immune cell involvement. Nonetheless, the hRO-AMD model could serve as a powerful tool to uncover novel therapeutic targets. In conclusion, this oxidative stress injury model of ROs can provide valuable insights for the development of new therapies for dry AMD via targeting HMOX1 and its downstream pathways.