Stem cell therapy reverses blindness in animals with end-stage retinal degeneration

January 10, 2017, Cell Press
Synaptic integration of graft retina into host mice. 3-D observation of contact between host bipolar cells (green) and graft retina (red). Credit: Mandai et al./Stem Cell Reports 2017

A stem cell-based transplantation approach that restores vision in blind mice moves closer to being tested in patients with end-stage retinal degeneration, according to a study published January 10 in Stem Cell Reports. The researchers showed that retinal tissue derived from mouse induced pluripotent stem cells (iPSCs) established connections with neighboring cells and responded to light stimulation after transplantation into the host retina, restoring visual function in half of mice with end-stage retinal degeneration.

"Our study provides a proof of concept for transplanting stem cell-derived retinal tissues to treat patients with advanced retinitis pigmentosa or ," says senior study author Masayo Takahashi of the RIKEN Center for Developmental Biology. "We are planning to proceed to clinical trials after some more additional studies, and hope to see these effects in patients as well."

End-stage is a leading cause of irreversible vision loss and blindness in older individuals. Typically, patients with conditions such as retinitis pigmentosa and age-related macular degeneration lose vision as a result of damage to the outer nuclear layer of light-sensitive photoreceptor cells in the eye. There is no cure for end-stage retinal degeneration, and currently available therapies are limited in their ability to stop the progression of vision loss.

One strategy to restore vision in patients who are blind from outer retinal degeneration is cell replacement. Toward that goal, Takahashi and her team recently showed that stem cell-derived retinal tissues could develop to form structured outer nuclear layers consisting of mature photoreceptors when transplanted into animals with end-stage retinal degeneration. But until now, it was not clear whether transplantation of these cells could restore visual function.

In the new study, Takahashi and first author Michiko Mandai of the RIKEN Center for Developmental Biology set out to address that question. To do so, they first genetically reprogrammed skin cells taken from adult mice to an embryonic stem cell-like state, and then converted these iPSCs into retinal tissue. When transplanted into mice with end-stage retinal degeneration, the iPSC-derived retinal tissue developed to form photoreceptors that established direct contact with neighboring cells in the retina.

"We showed the establishment of host-graft synapses in a direct and confirmative way," Mandai says. "No one has really shown transplanted stem cell-derived retinal cells responding to light in a straightforward approach as presented in this study, and we collected data to support that the signal is transmitted to host cells that send signals to the brain."

Moreover, almost all of the transplanted retinas showed some response to light stimulation. The key to success was to use differentiated retinal tissue instead of retinal cells, which most researchers in the field use. "The photoreceptors in the 3D structure can develop to form more mature, organized morphology, and therefore may respond better to light," Takahashi explains. "From our data, the post-transplantation retina can respond to light already at one month in mice, but since the human retina takes a longer time to mature, it may take five to six months for the transplanted retina to start responding to light."

Remarkably, this treatment strategy restored vision in nearly half of the mice with end-stage retinal degeneration. When these mice were placed in a box consisting of two chambers that independently delivered electric shocks on the floor, they were able to use a light warning signal to avoid the shocks by moving into the other chamber. "We showed that visual function could be restored to some degree by transplantation of the iPSC-derived retina," Mandai says. "This means that those who have lost light perception may be able to see a spot or a broader field of light again."

3-D observation of contact between GFP-positive host bipolar cells (green) and CtBP2-tdTomato in the graft outer nuclear layer (red). DAPI marks the cell bodies of the graft retinal sheet. Credit: RIKEN

To make the findings more applicable to patients, the researchers are currently testing the ability of human iPSC-derived retinal tissue to restore visual function in animals with end-stage retinal degeneration. If these experiments are successful, they will then test the safety of this protocol in part by assessing how the host retina responds to the graft. At the same time, they will continue to search for ways to increase the ability of graft photoreceptors to integrate with the host , with the ultimate goal of moving to clinical trials in humans.

"It is still a developing-stage therapy, and one cannot expect to restore practical vision at the moment," Takahashi cautions. "We will start from the stage of seeing a or large figure, but hope to restore more substantial vision in the future."

Explore further: Krembil research prompts rethink on established vision recovery theory

More information: Michiko Mandai et al, iPSC-Derived Retina Transplants Improve Vision in rd1 End-Stage Retinal-Degeneration Mice, Stem Cell Reports (2017). DOI: 10.1016/j.stemcr.2016.12.008

Related Stories

Krembil research prompts rethink on established vision recovery theory

December 14, 2016
A team of researchers at the Krembil Research Institute has published a paper that is expected to change the way scientists think about vision recovery after retinal cell transplantation.

Study suggests stem cells may repair dying retinal cells

January 21, 2016
Researchers at St. Erik Eye Hospital and Karolinska Institutet have for the first time successfully transplanted human retinal pigment epithelial cells derived from stem cells into eyes that are similar to human eyes. The ...

New research could lead to restoring vision for sufferers of retinal disorders

June 29, 2016
Engineers and neuroscientists at the University of Sheffield have demonstrated for the first time that the cells in the retina carry out key processing tasks. This could pave the way for improving retinal implants and therefore ...

A new mode of communication between donor and host photoreceptors in retinal dystrophy

October 24, 2016
UK eye researchers with funding from Fight for Sight have discovered a new means of communication between transplanted donor photoreceptors developed from stem cells and the degenerating photoreceptors of the host retina. ...

New insight into eye diseases

September 28, 2016
Many diseases that lead to blindness, such as glaucoma and macular degeneration, are caused by the death of certain cells in the human retina that lack the ability to regenerate. But in species such as zebrafish these cells, ...

Potential new approaches to treating eye diseases

February 4, 2016
Potential new approaches to treating eye diseases such as age-related macular degeneration (AMD) are described in a new study, "IL-33 amplifies an innate immune response in the degenerating retina," in the February Journal ...

Recommended for you

Outbreak of preventable eye infection in contact lens wearers

September 21, 2018
A new outbreak of a rare but preventable eye infection that can cause blindness, has been identified in contact lens wearers in a new study led by UCL and Moorfields Eye Hospital researchers.

Newly formed blood vessels may contribute to eye disease

September 14, 2018
Newly formed blood vessels may be cracks in the barrier between the bloodstream and the eye, according to a Northwestern Medicine study published in the Proceedings of the National Academy of Sciences.

Eye disease can cause blindness, and it's on the rise

August 29, 2018
A new study into recent cases of ocular syphilis warns increasing numbers of people are at risk of permanent damage to their vision.

INSiGHT identifies unique retinal regulatory genes

August 28, 2018
Vision begins in the retina, a light-sensing neural network in the eye that is critical for our ability observe the world around us. Researches at Baylor College of Medicine, Texas Children's Hospital and the Hospital for ...

Alzheimer's one day may be predicted during eye exam

August 23, 2018
It may be possible in the future to screen patients for Alzheimer's disease using an eye exam.

Researchers find potential new gene therapy for blinding disease

August 20, 2018
The last year has seen milestones in the gene therapy field, with FDA approvals to treat cancer and an inherited blinding disorder. New findings from a team led by University of Pennsylvania vision scientists, who have in ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.