Is This the Next Best Thing to Regrowing a New Retina?

Just as a salamander can grow a new tail, the human retina may be capable of regenerating cells that allow us to see detail and color–If we can unlock potential with the right technique and ‘code’ for regeneration.

BrightFocus Macular Degeneration Research grant recipient Juliette Wohlschlegel, PhD, plans to harness the blueprints to regeneration found in nature. But rather than attempting to regrow the entire retina, she is working on a way to replace certain light-detecting retinal cells that are destroyed byage-related macular degeneration (AMD).

This novel approach could provide hope to people facing severe vision loss due to advanced AMD. “It offers the potential to restore vision in the later stages of the disease,” noted Dr. Wohlschlegel. Current treatments must be used much earlier, since they only stabilize eyesight in most people.

Borrowing from Nature to Fuel Human Discoveries

Dr. Wohlschlegel is a neuroscientist with a deep drive to find potential treatments for people living with AMD. Her experience working in a geriatric hospital led her to pursue neuroscience as a student. She quickly became fascinated with vision research, a bond that grew even stronger after her own grandmother was diagnosed with AMD.

She expects her new study to reveal information that will bring the goal of developing better treatments for AMD one step closer. “I believe that findings from our work will pave the way to therapeutic strategies that can improve patients’ daily lives,” she said.

A handful of fish and amphibians have an amazing advantage over human beings and most other animals. If the retina in your eye is injured or damaged, a type of helper cell sets off a cycle of inflammation. This response typically leads to scarring and further damage. But a few species, including the small, striped zebrafish found in pet stores, respond to this type of trauma differently. They regrow a whole new retina. And those support cells—called Müller glia—play a key role in this renewal process.

In 2020, Dr. Wohlschlegel joined Dr. Thomas Reh’s lab at the University of Seattle in Washington. At the time, Dr. Reh (who is a leader in retinal regenerative medicine) and his team had already reached an important milestone toward the goal of restoring damaged retinal cells. They discovered that, under certain conditions, Müller glia in mice can transform into nerve cells or neurons.

Light-sensitive nerve cells known as cones give us clear color vision. In AMD, cone cells in the macula die. The macula is the tiny ‘bullseye’ in the center of the retina with the greatest number of cones. By building on her own work and that of Dr. Reh’s team, Dr. Wohlschlegel hopes to coax Müller glia to turn into cone cells.

Earlier research looking into why certain species can regrow the retina led to the discovery of a protein called Ascl1. Ascl1 allows immature neurons to develop into different types of mature, specialized nerve cells. When a zebrafish suffers injury or damage to the retina, the gene that makes Ascl1 goes into overdrive, unleashing a flood of the protein to kick-start the reprogramming. This repair process does not happen in mammals.

A Possible Path to Restoring Lost Vision

The next question was whether human retinal cells held the same potential to regenerate.

To find out, Dr. Wohlschlegel used human retinal cells taken from an organoid (a sort of mini-model of the retina). “We demonstrated that Müller glia derived from human retinal organoids can be reprogrammed into neurons,” Dr. Wohlschlegel said. But these new neurons, which were grown in a flat dish, did not keep their shape and stayed immature.

Next, Dr. Wohlschlegel’s team combined a method of growing cells in 3D with tools fine-tuned to target only Müller glia. This work showed “that Müller glia can be reprogrammed in 3D, and that the combination of factors influences the type of neurons the reprogrammed cells mature into,” Dr. Wohlschlegel explained.

Dr. Wohlschlegel’s current project is focused on finding a way to efficiently regenerate cone cells. “We will test different combinations of factors to promote cone production from human Müller glia,” she said.

Growing new cones from a person’s own Müller glia would avoid the drawbacks of more common approaches to replacing damaged retinal cells. Stem cell transplantation, for example, uses donor cells. To prevent the body from attacking the transplanted cells, people must take anti-rejection drugs. These medications make people more prone to serious infections and other health problems.

A Message From Dr. Wohlschlegel

Funding from Macular Degeneration Research has played an essential role in driving Dr. Wohlschlegel’s work forward. “It has had a significant impact on my research, enabling me to work more independently and concentrate on my own projects,” she said. Just as importantly, “it has provided me with the opportunity to join the vibrant community of BrightFocus researchers. I am truly honored and grateful to BrightFocus Foundation.”