Lauren Fuge
Korean researchers have developed a new method that might one day restore vision to patients with retinal disease.
“Our goal is to provide a solution for patients at risk of blindness who lack proper treatment options,” says Eun Jung Lee, from the Korea Advanced Institute of Science and Technology (KAIST).
Lee and team identified that a protein called Prox1 acts as a ‘molecular brake’ to prevent mammals from naturally regrowing damaged retinal neurons. They were then able to remove Prox1 in lab mice and reactivate retinal regeneration.
“The notion that retinal regeneration in mammals is actively suppressed … is a powerful and fascinating twist,” says Jason Limnios, leader of the Stem Cell Research Group at Bond University’s Clem Jones Centre for Regenerative Medicine, who was not involved in the study. “It suggests the regenerative machinery might still be present and – with the right intervention – could potentially be reactivated in humans.”
What is retinal disease?
The retina is a layer of light-sensitive tissue at the back of your eye. It captures the photons entering your eye and converts them into electrical signals to send to your brain. In fact, the retina is part of the brain and contains five types of neurons, including photoreceptor cells. When the retina is damaged, vision can be affected.
More than 300 million people around the world suffer from some form of degenerative retinal disease, such as glaucoma, age-related macular degeneration (AMD) or retinitis pigmentosa (RP), which can lead to vision impairment or loss. And as the population continues to age, retinal disease patients increase.
Currently, some treatments exist to slow the progression of disease, and there are a few strands of research into how to restore vision, including gene therapy, stem cell procedures, and even the promise of “bio-printing” new cells to replace damaged ones.
But this new research from KAIST, published in Nature Communications, looks at how to tap into the body’s own repair mechanisms.
Cold-blooded invertebrates like fish are able to regenerate their retinas when damaged. The injury triggers a process that turns Müller glia (support cells that help maintain the structural and functional stability of retinal cells) into retinal progenitor cells.
This occurs through dedifferentiation, where cells can develop in reverse. It’s a critical response to tissue damage, and is essentially a ‘re-programming’ where the cells can return to an earlier stage, then re-develop into what is needed.
But mammals lack this ability, and so are unable to regenerate the retina when damaged – although with a bit of help, this may change.
Finding the molecular brake
The KAIST team discovered that a powerful ‘molecular brake’ actively blocks the regeneration of retinal cells in mammals, by inhibiting the dedifferentiation process. The culprit is a protein called Prox1.
By looking at mice, the team found that Prox1 is secreted by retinal neurons and is transferred to the Müller glial cells, where it accumulates. They also examined the postmortem retinas of a person who had retinitis pigmentosa, and found a similar accumulation. In contrast, this accumulation of the protein is absent in zebrafish, which can freely regenerate its retinal cells.
But if Prox1 can be captured before it is transferred to the Müller glia, then the dedifferentiation process can proceed. Essentially, the KAIST team discovered that the ability for mammals to regenerate retinal cells is not absent, only silenced.
Using this knowledge, they developed a method to capture Prox1 before it reaches the Müller glia, by using an antibody – delivered by an adeno-associated virus injected into the eye – that binds to Prox1.
The team tested the method on mice. It successfully blocked Prox1 and allowed Müller glia to begin to regenerate, creating new photoreceptor cells and other retinal neurons in the mice.
The regeneration ability of the mice was not as impressive as the regeneration seen in zebrafish, suggesting there may be other barriers yet to be discovered. However, the effect lasted over six months, making this is the first time a long-term result for retinal regeneration has been demonstrated in mammals.
Seeing the future
“This is very exciting work,” says Raymond Wong, head of the Cellular Reprogramming Unit at the Centre for Eye Research Australia (CERA), who was not involved in the research. “The paper highlighted the potential of MG [Müller glia] reprogramming as a regenerative approach to treat blindness.
“To realise this potential, it will be important to evaluate the long-term safety of this MG reprogramming approach and demonstrate sustained efficacy in visual improvement in vivo. Future research in larger animal models would also be important to translate the findings in rodents to the patients.”
Bond University’s Limnios agrees, pointing out that several questions remain, including whether the same regeneration mechanism will work in humans.
“The study presents some human data showing Prox1 within Müller glia from diseased retinas, but not in healthy tissue,” he explains. “While this correlates well with observations in mice, it doesn’t necessarily mean Prox1 suppresses regeneration in the human retina, or that it’s the only suppressive factor at play.”
Limnios suggests that human retinal organoids – mini retinas grown in the lab from stem cells – could be used as test platforms to see whether Prox1 also inhibits regeneration in the human retina.
“[Organoids] allow researchers to explore treatments in a human-like system before moving to animal studies or clinical trials, helping to speed up and refine the development of therapies for blinding diseases like macular degeneration and retinitis pigmentosa,” he says.
And if Prox1 does act in humans like it does in mice, the next big question is how the protein moves between cells.
The method is being further developed by biotech startup Celliaz Inc., founded by KAIST members. They aim to start clinical trials by 2028.
Meanwhile, other researchers – like Wong’s group at CERA in Melbourne – are approaching this pressing problem from a slightly different angle.
“We are developing a gene therapy approach to reprogram MG cells to regenerate photoreceptors,” he says. “This work is now going through the commercialisation pathway with a CERA biotech spin-off Mirugen to drive further development of this MG reprogramming approach into a gene therapy to treat blindness.
“These are certainly exciting times in the retina reprogramming field.”