Scientists restore sight in mice and look ahead to human vision

A team of researchers has reversed congenital blindness in mice by changing supportive cells in the retina—called Müller glia—into rod photoreceptors. Their findings, which are published in Nature, advance efforts toward regenerative therapies for blinding diseases in humans such as age-related macular degeneration and retinitis pigmentosa.

“This is the first report of scientists reprogramming Müller glia to become functional rod photoreceptors in the mammalian retina,” said Thomas N. Greenwell, PhD, National Eye Institute (NEI) program director for retinal neuroscience. “Rods allow us to see in low light, but they may also help preserve cone photoreceptors, which are important for color vision and high visual acuity.”

In the later stages of eye diseases, the cones tend to die. If rods can be regenerated from inside the eye, then the stage may be set for treatment of diseases that affect photoreceptors, light-sensitive cells in the retina in the back of the eye that signal the brain when activated. In mammals, photoreceptors lack regenerative capacity and do not divide once mature.

In other species, however, such as zebrafish, Müller glia divide in response to injury and can turn into photoreceptors and other retinal neurons. As a result, zebrafish can regain vision after severe retinal injury.

In a laboratory setting, scientists have been able to coax mammalian Müller glia to behave more like they do in the fish, but it requires injuring the tissue.

“From a practical standpoint, if you’re trying to regenerate the retina to restore a person’s vision, it is counterproductive to injure it first to activate the Müller glia,” said lead investigator of the study, Bo Chen, PhD, associate professor of Ophthalmology, Neuroscience, and Developmental and Regenerative Biology, and director of the Ocular Stem Cell Program at the Icahn School of Medicine at Mount Sinai located in New York, NY.

Dr. Chen added: “We wanted to see if we could program Müller glia to become rod photoreceptors in a living mouse without having to injure its retina.”

In the first stage of a two-step reprogramming sequence, the team stimulated Müller glia division in normal mice by injecting the eyes with a gene to activate the protein beta-catenin. After two weeks, the investigators administered another injection with factors that encouraged the newly divided cells to develop into rod photoreceptors.

The researchers used microscopy to visually track the newly formed cells.

Results showed that the newly formed rod photoreceptors looked structurally equivalent to real photoreceptors, and synaptic structures, which allow the rods to communicate with other types of neurons within the retina, also formed. To determine whether the Müller glia-derived rod photoreceptors were functional, the investigators tested the treatment in mice born without functional rod photoreceptors.

In the treated blind mice, Müller glia-derived rods developed just as effectively as they had in mice without visual impairment. The team then confirmed that the newly formed rods were communicating with other types of retinal neurons across synapses.

Light responses recorded from retinal ganglion cells—neurons that transmit signals from photoreceptors to the brain—and measurements of brain activity confirmed that the newly formed rods were, indeed, integrating in the visual pathway circuitry, from the retina to the primary visual cortex in the brain.

While it is difficult to state with certainty how much vision was restored in the laboratory mice, it appears that they can perceive light. Dr. Chen’s laboratory is currently conducting behavioral studies to determine whether the mice have regained the ability to perform visual tasks such as navigating a water maze.

As for humans, Dr. Chen and his team have plans that include investigating whether the technique will work on cultured human retinal tissue. Much more work will need to be done in the meantime, including in animals with eyes more similar to ours.

The hope is that the technique will someday be used for restoring vision loss due to retinal disease in humans, or to prevent vision loss altogether.

The study was funded in part by the NEI, which is part of the National Institutes of Health.