Novel therapies targeting inflammation, cell reprogramming and metabolism are showing more promise than ever.
Forget one gene, one therapy—the future of retinal disease treatment may be universal.
Vision scientists are increasingly straying from the path of one-gene, one-treatment approaches to retinal degeneration in favor of broader, gene-agnostic strategies. At the annual meeting of The Association for Research in Vision and Ophthalmology 2025 (ARVO 2025), five pioneering researchers revealed how such strategies as manipulating inflammation, reprogramming glial cells, tweaking metabolism cycles and transplanting engineered cells could revolutionize treatment for millions worldwide suffering from blinding conditions.
With over 100 different genes linked to retinitis pigmentosa alone, and countless more involved in other retinal diseases, the gene-specific approach faces overwhelming challenges, especially in orphan diseases, where commercialization and funding for targeted approaches are limited. The novel gene-agnostic approaches on display in Salt Lake City for ARVO 2025 aim to protect, rescue, or replace retinal cells regardless of the underlying genetic defect, potentially offering more universally applicable treatments for retinal diseases.
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Harnessing inflammation for retinal regeneration
Dr. Muriel Perron’s (France) opening talk upended conventional wisdom about inflammation’s role in retinal regeneration. She described her team’s discovery that certain species of Xenopus frogs can regenerate their retina after injury through Müller cell reprogramming—and inflammation appears to be a key driver rather than a hindrance.
“We discovered a few years ago that actually Xenopus laevis can indeed regenerate its retina upon injury, thanks to Müller cells,” Dr. Perron explained. The presence of microglia, the retina’s immune cells, strongly correlated with Müller cell proliferative capacity—and her research followed this key insight.
By manipulating inflammatory conditions, Dr. Perron’s team transformed previously non-responsive cells into proliferative ones. They identified APOE (apolipoprotein E) as a crucial molecular player.
“APOE is one of these candidates because we found that its expression correlates with Müller cell proliferative capacity,” Dr. Perron noted. “Our knockout experiment suggests that it is required for a Müller cell proliferative response to injury in Xenopus. And it seems to be sufficient to trigger a Müller cell proliferative response in the mouse.”
These findings suggest that inflammatory signals, particularly APOE, may be therapeutically harnessed to stimulate retinal regeneration across species. Dr. Perron’s work challenges previous assumptions about inflammation in neural repair and opens new avenues for promoting regeneration in mammals with typically limited regenerative capacity.
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Reprogramming glial cells into functional neurons
Dr. Thanh Hoang (United States) demonstrated significant progress in reprogramming mammalian Müller glia into functional neurons. While zebrafish can naturally regenerate retinal cells, mammals have lost this ability. Dr. Hoang’s team found that simultaneously knocking out multiple factors—specifically Notch signaling components and NFI transcription factors—could trigger mammalian Müller cells to become neurons with remarkable efficiency.
When knocking out all these inhibitory factors together, around 65% of Müller cells transformed into neurons after injury. His team also developed a more streamlined approach using Neurog2 overexpression, which converted approximately 25% of Müller cells into neurons even without injury.
The reprogrammed cells primarily differentiated into bipolar and amacrine cells, with occasional rod photoreceptors. Importantly, electrophysiological recordings confirmed these new neurons responded to light stimuli and formed connections with existing retinal circuits. Dr. Hoang has extended this work to human retinal explants and is optimizing protocols to generate specific neuron subtypes for targeted replacement therapies.
“I’m very glad to see the growth of reprogramming topics in this conference. I remember when I was a postdoc a few years ago, there were only a handful of posters and talks on this. And now, especially in this conference, this increased exponentially,” he said. “My hope is that we all work together to finally push regeneration therapy to be reality in the next few years.”
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Preserving cones through metabolic intervention
Dr. Yunlu Xue (United States) demonstrated how manipulating metabolic pathways could preserve cone photoreceptors in retinitis pigmentosa (RP). His work targets TXNIP, a protein that regulates glucose transport and mitochondrial function.
“In RP, for some reason, glucose gets trapped in the RPE, so they are having trouble reaching the cone photoreceptors,” Dr. Xue explained. “This is causing some sort of starvation of the cones in RP condition.”
By overexpressing TXNIP in cones or a modified version in the retinal pigment epithelium, his team achieved substantial cone preservation and maintained visual function across multiple mouse models of retinitis pigmentosa. The approach helped cells switch from glucose to lactate metabolism when glucose availability was limited.
“TXNIP is a great therapy,” Dr. Xue said in conclusion. “The C terminus of TXNIP in RPE removes GLUT1 and rescued RP cones. Full TXNIP is thus still one of the most potent alleles when put into the cones.”
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CRISPR approaches to metabolic pathways
Dr. Stephen Tsang (United States) presented a variety of innovative CRISPR-based approaches targeting metabolic regulation in the retina. His research revealed the crucial metabolic coupling between photoreceptors and retinal pigment epithelium.
“Photoreceptors mix lactate, and then you need the RPE to consume the lactate,” Dr. Tsang explained. “You need a balance between production and consumption.”
Dr. Tsang’s clinical insights came from an unexpected source—patients with thalassemia taking iron chelators who developed retinal degeneration. This led to the discovery that hypoxia-inducible factors (HIFs) play a critical role in retinal metabolism.
Using CRISPR to ablate HIF pathway components in either photoreceptors or RPE cells, his team demonstrated improved photoreceptor survival and function across multiple retinal degeneration models, including phosphodiesterase and rhodopsin mutations.
“This may be a fruitful area for gene-agnostic treatment,” Dr. Tsang concluded, emphasizing the therapeutic potential of metabolic reprogramming without addressing the primary genetic defect.
Stem cell transplantation advances
With the last talk, Dr. Michiko Mandai (Japan) shared her team’s progress in stem cell-based retinal replacement therapy. Her team has successfully transplanted human pluripotent stem cell-derived retinal organoids into patients with advanced retinal degeneration, with some grafts surviving for nearly four years.
“These images really motivate me to find the key to consistently reproducing this type of integration,” Dr. Mandai said, showing striking images of transplanted cells integrating with host retinas.
Building on promising initial clinical experiences, Dr. Mandai’s team developed genome-edited organoids with fewer inner retinal cells to improve integration. “We’re moving on to the genome-edited type of brain grafts where we are trying to delete these inner graft bipolar cells which sometimes seem to impede the contact between the host bipolar cells and the graft photoreceptors,” she explained.
The modified organoids showed enhanced integration in both rodent models and non-human primates. Detailed electron microscopy analysis revealed host bipolar cells extending dendrites to form functional synaptic connections with transplanted photoreceptors—a crucial step for vision restoration.
“If we find a good timing, it’s quite likely that the host can be activated,” Dr. Mandai concluded. “The use of genome-edited retinal organoid sheets is a promising option for regenerative therapy in human retinal degeneration including macular degeneration.”
A complementary toolkit for retinal repair
Collectively, these presentations highlighted complementary approaches that could work in tandem to address the complex challenges of retinal degeneration.
While each approach on display remains at different stages of development—from basic research to early clinical trials—the session demonstrated tantalizing progress toward treatments that could transform the landscape of retinal disease management in the coming years along with the lives of the patients who need such therapies most.
READ MORE: Get the biggest stories in ophthalmology straight from ARVO 2025—right here.
Editor’s Note: Reporting for this story took place during the annual meeting of The Association for Research in Vision and Ophthalmology (ARVO 2025) being held from 4-8 May in Salt Lake City, Utah, United States.
