Supported by the PRO RETINA-Foundation for the Prevention of Blindness, the project brings together the expertise of Prof. Dr. Marius Ueffing, Director of the Institute for Ophthalmic Research (IOR) at the University of Tübingen, and Dr. Blanca Arango-Gonzalez (IOR), a retinal researcher whose work has significantly advanced the understanding of retinal degeneration. The project is conducted in close collaboration with Prof. Patricia Boya at the University of Fribourg (Switzerland), with additional contributions from Dr. Angela Armento (IOR), whose previous work on age-related macular degeneration (AMD) helped establish important conceptual foundations.

Addressing a Common Challenge in Retinal Diseases

Retinal degenerative disorders such as Retinitis Pigmentosa (RP) and Age-related Macular Degeneration (AMD) progressively destroy photoreceptor cells, ultimately leading to irreversible vision loss. Despite remarkable advances in genetics and molecular biology, effective treatments capable of slowing disease progression remain limited.
Photoreceptors are among the most metabolically active cells in the human body. Every day they must continuously renew their light-sensitive outer segments while producing large quantities of highly specialized proteins. These demanding processes require an exceptionally stable supply of cellular energy generated by mitochondria—the cell's powerhouses.
When mitochondrial function declines, the delicate balance between energy production and protein quality control is disrupted. Oxidative stress increases, regenerative cellular functions deteriorate, and the cells gradually lose their ability to survive. This sequence of events is now recognized as a central mechanism driving retinal degeneration in both inherited and age-related diseases.

Combining Two Protective Mechanisms

The new project explores whether targeting two complementary cellular defense mechanisms simultaneously could provide greater protection than either approach alone.
Researchers in Tübingen have previously demonstrated that pharmacological inhibition of Valosin-Containing Protein (VCP), a key regulator of protein quality control, can significantly reduce retinal degeneration in experimental models of Retinitis Pigmentosa. Treated animals showed markedly improved visual function, and this therapeutic strategy is currently progressing toward clinical translation (RD TREAT).
The second approach focuses on improving mitochondrial quality control through mitophagy, the natural process by which damaged mitochondria are selectively removed and replaced. Previous studies from Prof. Boya's laboratory have shown that Urolithin A, a naturally occurring mitophagy activator, protects retinal cells from oxidative stress, reduces photoreceptor degeneration, and improves structural stability. Particular attention is being given to the BNIP3/NIX signaling pathway, whose role in retinal biology has not yet been fully understood.

Investigating Potential Synergy

Because protein homeostasis and mitochondrial quality control are closely interconnected, the investigators believe that combining both therapeutic approaches may produce synergistic benefits.
Using ex vivo retinal models and advanced human retinal pigment epithelium (RPE)-neural retina co-culture systems, the team will systematically investigate how mitochondrial dysfunction, impaired protein quality control, and photoreceptor loss interact during disease progression.
For the first time, the researchers will test whether combining pharmacological VCP inhibition with mitophagy activation through Urolithin A provides stronger neuroprotective effects than either treatment alone.

Building the Foundation for Future Therapies

The PRO RETINA Foundation's support serves as essential seed funding, enabling the participating laboratories in Tübingen and Fribourg to initiate key experimental studies and strengthen scientific collaboration.
As the project is still in its early stages, its primary objective is to improve the mechanistic understanding of retinal degeneration rather than to develop an immediate clinical treatment. Nevertheless, the knowledge gained is expected to provide a solid scientific foundation for larger future studies and may ultimately identify new therapeutic targets capable of preserving vision in patients affected by retinal degenerative diseases.