From left: Postdoctoral Fellows Xinzheng Guo, PhD, and Ye Xie, PhD, with Bo Chen, PhD.

A team of researchers, led by Bo Chen, PhD, Associate Professor of Ophthalmology, Icahn School of Medicine at Mount Sinai, has reversed congenital blindness in mice by changing the supportive Müller glia cells in the retina into functional rod photoreceptors—light-sensitive cells in the retina that signal the brain when activated.

The breakthrough research, published online in the August 15, 2018, issue of Nature, is expected to advance efforts toward retinal regeneration for diseases of the eye, such as age-related macular degeneration, degenerative glaucoma, and retinitis pigmentosa.

Funded in part by the National Eye Institute (NEI), an arm of the National Institutes of Health, the study drew praise from NEI Program Director Thomas N. Greenwell, PhD. “This is the first report of scientists reprogramming Müller glia to become functional rod photoreceptors in the mammalian retina,” says Dr. Greenwell. “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. Cones tend to die in later-stage eye diseases.  If rods can be regenerated from inside the eye, this might be a strategy for treating diseases of the eye that affect photoreceptors.”

Macro view of retinal stem cells in the process of division.

Scientists have long studied the regenerative potential of Müller glia cells because in species such as zebrafish, they divide in response to injury and can turn into photoreceptors and other retinal neurons. In the lab, scientists have coaxed mammalian Müller glia to behave as they do in the fish, but not without injuring the tissue. Since injured tissue is counterproductive to restoring vision, Dr. Chen’s lab was able to achieve an effective method of achieving both goals, something others could not.

In pursuing this novel gene-transfer therapy, Dr. Chen, who is also Director of the Ocular Stem Cell Program at the Icahn School of Medicine at Mount Sinai, and his investigators followed a two-stage process. First, they demonstrated that Müller glia cells could be spurred to divide in mice by injecting their eyes with a gene to turn on a protein called beta-catenin. Then, weeks later, the mice were injected with transcription factors Otx2, Crx, and Nrl that encouraged the newly divided cells to develop into rod photoreceptors.

The investigators were encouraged to find that the newly formed cells looked structurally no different from real photoreceptors, and that synaptic structures that allow the rods to communicate with other types of neurons within the retina had also formed.

When the researchers took another step forward by testing the treatment in congenitally blind mice that were born without functional rod photoreceptors, the results were positive once again. The light responses recorded from retinal ganglion cells—neurons that carry signals from photoreceptors to the brain—and measurements of brain activity confirmed that the newly formed rods were integrating into the visual pathway circuitry, from the retina to the primary visual cortex in the brain.

“Our findings underscore that we are closer than ever to developing new therapies for people with severe degenerative eye disease,” says Dr. Chen. “Mice that were blind from birth were now able to see light for the first time following treatment.”

Dr. Chen says his next step will be determining whether the technique works on cultured human retinal tissue. In addition to receiving NIH funding, Dr. Chen’s research was supported by a $2 million grant from the McGraw Family Foundation.

Benjamin D. Greenbaum, PhD

Immunotherapy has been a game changer in treating some cancers, but it does not work for every patient. Building mathematical models that might predict a patient’s response is central to the work of Benjamin D. Greenbaum, PhD, Assistant Professor of Medicine (Hematology and Medical Oncology), Oncological Sciences, and Pathology, at The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai. For his efforts, he recently won the Pershing Square Sohn Prize for Young Investigators in Cancer Research.

Dr. Greenbaum, a computational biologist, was among seven researchers to receive the award from the Pershing Square Sohn Cancer Research Alliance, a program of The Pershing Square Foundation. His laboratory will receive $200,000 yearly for the next three years. In a novel partnership, The Mark Foundation for Cancer Research will fully fund Dr. Greenbaum’s award, and has named him a Pershing Square Sohn Mark Foundation Fellow.

Dr. Greenbaum’s work “will be instrumental in understanding what types of T cells are required for generating effective anti-tumor immunity and how to design immune therapies that selectively induce their development,” says a longtime colleague and mentor, Nina Bhardwaj, MD, PhD, the Ward-Coleman Chair in Cancer Research, and Director of Cancer Immunotherapy, at The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai.

Dr. Greenbaum began his career studying the evolution of viruses and later became interested in checkpoint blockade inhibitor immunotherapies, which help the body recognize and kill cancer cells, and for which the Nobel Prize was recently awarded. He led a group that created the first predictive mathematical model demonstrating how a set of melanoma and lung cancer patients would respond to certain immunotherapies, a finding described in November 2017 in the journal Nature. To further improve such models, “we work with clinicians, oncologists, immunologists, geneticists, and others to try to round out the full picture of how the immune system interacts with cancer,” Dr. Greenbaum says. “This is a very vibrant time in cancer immunotherapy.”