ABOVE: Different cell types within the retina of the eye

Researchers report they have used retinal cone photoreceptors derived from human stem cells to restore vision in mice with advanced retinal degeneration. They are now designing a clinical trial to test whether transplanting healthy cone photoreceptors into people with age-related macular degeneration will improve their vision. 

Other studies have transplanted retinal cells derived from stem cells into patients with macular degeneration, but this latest work in mice transplanted cone photoreceptors rather than retinal pigment epithelium.   

“The reason we focus on cones is because they’re the most important for human vision,” says Robin Ali, who studies cell and gene therapy at King’s College London and led the study, which appeared April 20 in Cell Reports. Ali contrasts the role of cones, which enable us to recognize colors, discern other people’s faces, and see in a brightly lit room, to that of rods, a type of photoreceptor that works in dim light and helps with peripheral vision. While people with rod degeneration may experience tunnel vision, Ali says, people with cone degeneration may go completely blind. 

The most common eye disease linked to cone decay is macular degeneration. “If you live to be old enough, you’ll have some form of macular degeneration,” Ali says. Ophthalmologists can sometimes slow the disease’s progression, but they cannot yet reverse visual decline. 

Ali and colleagues wanted to know if stem cells differentiated into cone photoreceptors could restore some degree of vision in mice with inactive cones. They developed two variants of human cones: one derived from embryonic stem cells that functioned and looked normal, and a control type that appeared normal but could not respond to light. These control cones were derived from the peripheral blood of a 40-year-old person with achromatopsia, a condition that leads to partial or complete loss of color vision. 

Ali’s team transplanted the cones into the retinas of mice bred to develop advanced eye disease, with completely nonfunctional cones. Using these mice controlled for the possibility that residual function from existing cones, rather than the newly transplanted cones, was responsible for any improvements in vision. To ensure that the mice did not mount an immune defense against the human cells, they were also bred to be immunodeficient. 

The researchers injected functional cones into the retinas of 32 mouse eyes, and the aberrant cones into another 23 eyes. Sometimes both eyes of a mouse received the transplants, sometimes only one. Both types of cones, whether they functioned or not, attached to the retinas to form a cell mass that is typical of healthy eyes and necessary for seeing in bright light. 

But the similarities ended once researchers exposed the mice to light. The retinas of mice with functional human cones responded to light during an eye test designed to measure this, known as a microelectroretinogram, while the retinas of those with dysfunctional cones did not. In another test, the mice that had received the functional cones chose to retreat to a dark room when given the option, an indication the nocturnal animals were sensing the light and avoiding it as mice typically do. Mice with deficient cones, by contrast, remained in the light for much of the time. 

“I’m just impressed by the study. The kind of controls these authors have done—the lengths they have gone to make sure it is a complete, pure response to the transplanted cells, is just amazing,” says Hemant Khanna, an ophthalmologist at the University of Massachusetts Medical School who was not involved in the project. Khanna says he thinks this study sets a new bar for experimental design that similar work will need to meet in the future. 

“It’s taken us twenty years to actually get to the point of this study, which I’m really excited about,” Ali says, calling it a proof of concept that transplanted cones have the capacity to improve vision. While Ali notes that the capacity for manufacturing cones at scale does not yet exist, he is confident that his lab can produce enough cones for a human clinical trial. His next step is to recruit 16 participants in the United Kingdom in the next few years. 

Ophthalmologist Sai Chavala of the University of North Texas Health Science Center points out that one concern with a stem cell–derived transplant is that it can take a while for stem cells to mature into the cells that will be transplanted. In a 2020 study in Nature, Chavala and colleagues showed that it is possible to convert mouse skin cells directly into photoreceptors that can be transplanted into mouse retinas, rather than first converting the skin cells into induced pluripotent stem cells. In that study, the skin cells were converted into rods rather than cones.  

J. Ribeiro et al., “Restoration of visual function in advanced disease after transplantation of purified human pluripotent stem cell-derived cone photoreceptors,” Cell Rep, doi:10.1016/j.celrep.2021.109022, 2021.