Eye on the prize: two stem cell studies restore vision in blind mice

For the 39 million people in the world who are blind, a vision-restoring therapy would be the ultimate prize. So far, this prize has remained out of reach, but two studies published this week have entered the ring as promising contenders in the fight against blindness.

In the red corner, we have a study published in Stem Cell Reports from the RIKEN Institute in Japan led by scientist Masayo Takahashi. Her team restored vision in blind mice with an advanced stage of retinal disease by transplanting sheets of light-sensing photoreceptor cells that were made from induced pluripotent stem cells (iPSCs).

In the blue corner, we have a study published in Cell Stem Cell from the Buck Institute in California led by scientist Deepak Lamba. His team restored long-term vision in blind mice by transplanting embryonic stem cell-derived photoreceptor cells and preventing the immune system from rejecting the transplant.

Transplanting Retinal sheets

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Synaptic integration of graft retina into model mouse
Credit: RIKEN

Let’s first talk about the Riken study led by Masayo Takahashi. She is well known for her pioneering work on iPSC-derived treatments for macular degeneration – a disease that damages the retina and causes blindness.

In previous work, Takahashi and her team transplanted sheets of mouse stem cell-derived retinal progenitor cells, which mature into light-sensing cells called photoreceptors, into the eyes of mice. The cells within the sheet formed connections with the resident cells in the mouse eye, proving the feasibility of transplanting retinal sheets to restore vision.

In their current study, published in Stem Cell Reports, Takahashi’s team found that the retinal sheets could restore vision in mice that had a very severe form of retinal disease that left them unable to see light. After the mice received the retinal transplants, they responded to light, which they were unable to do previously. Like their other findings, they found that the cells in the transplant made connections with the host cells in the eye including nerve cells that send light-sensing signals to the brain.

First author on the study, Michiko Mandai explained the importance of their findings and their future plans in a news release,

“These results are a proof of concept for using iPSC-derived retinal tissue to treat retinal degeneration. We are planning to proceed to clinical trials in humans after a few more necessary studies using human iPSC-derived retinal tissue in animals. Clinical trials are the only way to determine how many new connections are needed for a person to be able to ‘see’ again.”

While excited by their results, Mandai and the rest of the RIKEN team aren’t claiming the prize for a successful treatment that will cure blindness in people just yet. Mandai commented,

“We cannot expect to restore practical vision at the moment. We will start from seeing a simple light, then possibly move on to larger figures in the next stage.”

Blocking the immune system

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Image showing transplanted GFP-expressing human stem cell derived photoreceptors (green) integrated in a host rodent retina stained for Otx2 (red).
Credit Jie Zhu, Buck Institute for Research on Aging

In the Buck Institute study, Lamba and his team took on the challenge of answering a controversial question about why retinal cell transplants typically don’t survive long-term in the eye. Some scientists think that the transplanted cells die off over time because they don’t integrate into the eye while others think that they are rejected and killed off by the immune system.

To answer this question, Lamba transplanted human embryonic stem cell-derived retinal cells into immunodeficient mice that lacked a protein receptor that’s vital for a functioning immune system. The retinal cells transplanted into immunodeficient mice survived much better than retinal cells transplanted into normal mice and developed into ten times as many photoreceptors that integrated themselves into the host eye.

Their next step was to transplant the retinal cells into mice that were blind and also lacked the same immune receptor as the other mice. After the transplant, the blind mice became responsive to light and showed brain activity associated with sensing light. Their newfound ability to see lasted for nine months to a year following the transplant.

Lamba believes that backing down the immune response is responsible for the long-term vision restoration in the blind mice. He explained the importance of their findings in a Buck Institute news release,

“That finding gives us a lot of hope for patients, that we can create some sort of advantage for these stem cell therapies so it won’t be just a transient response when these cells are put in, but a sustained vision for a long time. Even though the retina is often considered to be ‘immune privileged,’ we have found that we can’t ignore cell rejection when trying to transplant stem cells into the eye.”

In the future, Lamba will explore the potential for using drugs that target the specific protein receptor they blocked earlier to improve the outcome of embryonic stem cell-derived retinal transplants,

“We can also potentially identify other small molecules or recombinant proteins to reduce this interleukin 2 receptor gamma activity in the body – even eye-specific immune responses – that might reduce cell rejection. Of course it is not validated yet, but now that we have a target, that is the future of how we can apply this work to humans.”

Who will be the winner?

The Buck Institute study is interesting because it suggests that embryonic stem cell-based transplants combined with immunosuppression could be a promising strategy to improve vision in patients. But it also begs the question of whether the field should focus instead on iPSC-based therapies where a patient’s own stem cells are used to make the transplanted cells. This strategy would side step the immune response and prevent patients from a taking a lifetime of immunosuppressive drugs.

However, I’m not saying that RIKEN’s iPSC-based strategy is necessarily the way to go for treating blindness (at least not yet). It takes a lot of time and money to make iPSC lines and it’s not feasible given our current output to generate iPSC lines for every blind patient.

So, it sounds like a winner in this fight to cure blindness won’t be announced any time soon. In the meantime, both teams need to conduct further preclinical studies before they can move on to testing these treatments in human clinical trials.

Here at CIRM, we’re funding a promising Phase 1 clinical trial sponsored by jCyte for a form of blindness called Retinis Pigmentosa. Based on preliminary results with a small cohort of patient, the treatment seems safe and may even be showing hints of effectiveness in some patients.

Ultimately, more is better. As the number of stem cell clinical trials for blindness grows, the sooner we can find out which therapies work best for which patients.

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