For decades, the root causes of dry age-related macular degeneration have been a black box. We have observed its effects, the slow breakdown of the macula and the loss of the central vision needed for reading and detail, but we could not see the precise mechanisms of the disease. This has stalled progress in finding a treatment for what is a complex, multifactorial condition.

A newly published laboratory study provides a clearer view, identifying a specific gene that helps protect the retina. While this is not a patient-ready cure, it offers a promising actionable target for developing new therapies.

We first needed a better model

To see inside the black box, scientists engineered a new tool: the human retinal organoid. This miniature, functioning replica of human retinal tissue, grown from stem cells, self-assembles into the retina’s layered structure and lets researchers study disease mechanisms in unprecedented detail.

While this model is a significant advance, it remains an early-stage platform; it lacks the blood vessels and immune cells of a complete eye and cannot replicate the chronic, decades-long timescale of AMD in a person.

The model confirmed the attacker

Using the organoids, researchers induced intense oxidative stress, a cellular imbalance long believed to be a primary attacker in dry AMD, and directly observed this stress driving programmed cell death in retinal cells, confirming a long-held theory in a human-tissue model.

Having validated the process, they screened two existing compounds, metformin and TN1, and found that both significantly reduced cell death, shielding the vital retinal cells from damage.

A specific defence system was identified

The critical question was not just that the shield worked, but how. Deep genetic analysis showed that both compounds protected the cells by activating the same defence system: a gene called HMOX1, which encodes the antioxidant enzyme heme-oxygenase-1.

This finding is valuable because it links the drugs’ protective effects to a defined biological pathway. However, it is not the first actionable target for dry AMD; complement-pathway inhibitors such as pegcetacoplan (Syfovre) and avacincaptad pegol (Izervay) have already reached the clinic.

What this discovery means for treatment

This work provides a clear, scientifically grounded path forward, but it remains a starting point. Future therapies will need careful control, as animal studies show that while moderate activation of HMOX1 is protective, prolonged high-level expression can damage the retina.

The fact that one compound, metformin, is already widely used is encouraging for repurposing, although key questions about getting sufficient drug to the retina remain unanswered.

Ultimately, this research shifts the objective from battling a poorly understood condition to learning how to safely modulate a specific, identified defence mechanism within the eye, alongside other validated pathways such as complement.

Sources

• Human retinal-organoid dry-AMD model & HMOX1 up-regulation — Genes & Diseases, 2025

• Metformin/TN1 screen press release — EurekAlert!, 9 Jul 2025

• High-dose HO-1 toxicity in photoreceptors — Li et al., Antioxidants, 2021

• Metformin efficacy for AMD systematic review — Huh et al., Ophthalmology Science, 2025