A New Macular Degeneration Suspect: The Eye's Light-Sensing Cells

Inside the retina, a layer of cells called the retinal pigment epithelium (RPE) works around the clock to clear waste from neighboring photoreceptors, the cells that sense light. In people with age-related macular degeneration (AMD), that cleanup system breaks down, and the debris left behind is often blamed on the RPE. Now, a new study published in Molecular Therapy Nucleic Acids led by Macular Degeneration Research grant recipient Claudio Punzo, PhD, points to a different culprit: the photoreceptors themselves¹.

Dr. Punzo, associate professor and vice chair for research at the University of Massachusetts Medical School, and his team found that as photoreceptors age, they can mismanage the fats that make up their cell membranes, setting off a chain reaction that leads to toxic debris buildup. Using a new model of AMD, Dr. Punzo’s team has developed a gene-silencing therapy that reversed this process for as long as six months, opening up a potential new way to treat a disease that currently has few good options.

A gut feeling leads to a discovery

The research emerged from a hunch Dr. Punzo had while studying a different type of retinal disease. “It was initially an intuition that was driven in part from lessons I learned about photoreceptors,” he said. That work taught him how photoreceptors respond when they’re deprived of nutrients.

For years, the field has largely treated photoreceptors as innocent casualties of the disease, affected by the RPE deteriorating around them rather than playing an active role in retinal damage. Dr. Punzo suspected otherwise.

Photoreceptors are naturally rich in fats, which they use to hold the proteins essential for vision. As people age, the fat makeup of those cells shifts slightly, which is a normal part of getting older. But in people with AMD, that shift is far more pronounced, and Dr. Punzo’s team suspected it’s this exaggerated change that ultimately overwhelms the RPE’s ability to clear waste.

New models and treatments for AMD

To test that idea, Dr. Punzo’s lab first needed a better model to study AMD. His team created a new model to mimic the same changes seen in human photoreceptor tissue. This model went on to develop an advanced form of AMD at a similar rate to humans.

With the model in hand, Dr. Punzo’s team developed a gene-silencing therapy delivered by a single injection that dialed down a gene controlling how photoreceptors manage fats. In treated models, the therapy reduced the buildup of fatty deposits at the back of the eye and reversed the early markers of AMD.

If the same single-injection therapy works in people, it could be a gamechanger. Current AMD treatments typically require injections every month or two, limiting their accessibility.

“This is a burden for elderly people and their family members who often have to drive them to the doctor’s appointment, and the injection is not the most comfortable procedure,” Dr. Punzo said. “Any reduction in frequency is a direct improvement in the quality of life of these patients.”

The work’s impact goes beyond this single therapy. By identifying photoreceptors as active drivers of disease, Dr. Punzo’s research could reframe how scientists think about AMD altogether, allowing them to treat the root cause of the disease rather than just its symptoms.

“This is similar to treating a cold with medicine that reduces coughing or sneezing rather than with medicine that destroys the virus directly,” Dr. Punzo said.

From the lab to the clinic

The next step for this research is determining whether the treatment works in people. Alongside university colleagues, Dr. Punzo helped launch a company to carry the work forward. The company’s mission is reflected in its name: Trinetra, after the all-seeing third eye of the Hindu deity Shiva. The next planned milestone is a large-scale preclinical safety trial.

Dr. Punzo’s discovery is one piece of Macular Degeneration Research’s 360-degree approach, with research funding for cell metabolism, debris formation, genetics, and cell regeneration. That range of strategies means that each discovery can play off each other, paving the way for the whole field.

None of his own work would have been possible, Dr. Punzo said, without early support from Macular Degeneration Research.

“With money being tight, we researchers often face the problem of deciding whether to follow some of our instincts and test something new or just go down the safe and established road where continued funding is easier to obtain,” Punzo said. “Without this seed money, many great ideas die in the minds of researchers, and we don’t find out if they were worth pursuing.”

“Every dollar you donate may help someone translate an idea into real data,” Dr. Punzo added, “which hopefully at one point becomes a translatable therapy.”

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