Ocular Degeneration Mechanisms and Therapeutic Approaches

Ocular degeneration encompasses a spectrum of disorders characterised by progressive loss of retinal structure and function, often culminating in irreversible vision impairment. Core mechanisms include genetic mutations affecting photoreceptor proteins, oxidative stress in the retinal pigment epithelium (RPE), dysregulated autophagy, chronic inflammation mediated by microglia and complement activation. Progressive photoreceptor loss triggers remodelling of inner retinal circuits and changes in retinal ganglion cell activity. Therapeutic strategies under investigation range from gene replacement and neuroprotective molecules to cell-based therapies and advanced retinal prostheses. Gene therapy can restore or replace defective genes using viral vectors, while small molecules aim to reduce oxidative stress and modulate autophagy. Stem cell approaches seek to replenish lost RPE and photoreceptors, and implantable microelectrode arrays or light-sensitive electronic devices offer potential vision restoration in end-stage disease. Together, these avenues promise to address both underlying pathophysiology and functional rehabilitation, with global implications for preventing blindness in ageing and inherited retinal disorders.

Research from Nature Portfolio

Recent studies have advanced gene therapy for inherited retinal degeneration by testing an AAV2-based vector delivering REP1 in patients with choroideremia. Although the phase 3 trial did not meet its primary visual acuity endpoint, safety was affirmed and secondary analyses indicated modest functional gains, highlighting the need to refine patient selection criteria, vector dosing and surgical delivery to enhance efficacy. In parallel, innovations in retinal prostheses have emerged through the integration of ultrathin, liquid-metal microelectrode arrays with soft photosensitive transistors. These devices achieve closer proximity to retinal ganglion cells, reduced impedance and improved charge injection, enabling robust evoked responses in a model of retinal degeneration. Utilising unsupervised machine learning to decode neural activity further supports the prospect of finely tuned, implantable systems for vision restoration in blind patients.

Ocular Degeneration Mechanisms and Therapeutic Approaches publication trend

The graph below shows the total number of articles in ocular degeneration mechanisms and therapeutic approaches across all publications each year (not limited to Nature Index journals).

Technical terms

Photoreceptors: Light-sensitive cells in the retina (rods and cones) responsible for converting light into neural signals.

Retinal pigment epithelium (RPE): A monolayer of cells that supports photoreceptors by recycling visual pigments and regulating oxidative stress.

Gene therapy: A strategy to treat disease by delivering functional genetic material to patient cells, often via viral vectors.

Retinal prosthesis: An implantable device designed to restore vision by electrically stimulating retinal neurons.

Autophagy: A cellular process that degrades and recycles damaged proteins and organelles to maintain homeostasis.

Microglia: Resident immune cells of the central nervous system, including the retina, that can mediate inflammation and phagocytosis.

Subretinal injection: A delivery method placing therapeutic agents directly between the retina and underlying tissue.

References

1. Subretinal timrepigene emparvovec in adult men with choroideremia: a randomized phase 3 trial. Nature Medicine (2023).
2. Liquid-metal-based three-dimensional microelectrode arrays integrated with implantable ultrathin retinal prosthesis for vision restoration. Nature Nanotechnology (2024).
3. Gene replacement therapy in Bietti crystalline corneoretinal dystrophy: an open-label, single-arm, exploratory trial. Signal Transduction and Targeted Therapy (2024).
4. Dysfunctional autophagy in RPE, a contributing factor in age-related macular degeneration. Cell Death & Disease (2017).
5. Microglial phagocytosis of living photoreceptors contributes to inherited retinal degeneration. EMBO Molecular Medicine (2015).