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Mini-retinas model human disease in a dish

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Mini-retinas model human disease in a dish

diabetic retinopathy, and retinitis pigmentosa are more common, yet physicians have little to offer patients who have lost their rods, cones, and other retinal cells. 

Back in 2006, Valeria Canto-Soler, then an eye researcher at Johns Hopkins University, used animal models and cell cultures to investigate the retina, but these models were disappointingly inadequate. Two-dimensional cell cultures could not approximate intricate 3D retinas packed with layers of discrete cell types living in a rich physical environment, and animal models did not accurately represent retinal anatomy and human disease pathogenesis.

Then, unexpectedly, there was “a revolution in the field,” said Canto-Soler. Cell biologists Kazutoshi Takahashi and Shinya Yamanaka at Kyoto University introduced four factors into mammalian cells and turned back time, reversing differentiation and allowing adult fibroblasts to become any cell in the body. They called these induced pluripotent stem (iPS) cells (1). “That’s the time when I started to think about the possibility of using human iPS cells to generate a 3D tissue that would resemble as close as possible the retinal tissue,” said Canto-Soler.

Motivated by the lack of adequate treatment options for patients with retinal degenerative diseases, Canto-Soler started her own research group at Johns Hopkins University to try to address this unmet need. She and her team got to work using iPS cells to generate 3D retinal tissues. They studied and manipulated iPS cells for years, while other research groups made strides with embryonic stem cells. 

Canto-Soler’s group kept pushing. Finally, they hit the jackpot: In 2014, they published the first paper showing that iPS cells could self-assemble into a 3D retinal organoid with all the cell layers in the right order and photoreceptors sensitive to light (2). 

“That’s the time when I started to envision a bigger program, not just my lab,” she said. “A team of investigators that would have complementary expertise, that will know the things that I didn’t know… Can we translate these into retinal transplants to restore vision in patients who are blind because they have lost their photoreceptors?” 

Building the team: disease models and drug screening

At the same time as Canto-Soler worked on her iPS cell research, a philanthropic family led by Diane Gates Wallach and her brother John Gates, committed to fund new research in regenerative medicine, with a special interest in age-related macular degeneration (AMD). The family patriarch and former CEO of the Gates Rubber Company, Charles Gates Jr., had suffered from AMD and blindness at the end of his life, so they developed the Gates Center for Regenerative Medicine at the University of Colorado. 

Once the technology for easily creating iPS cells was developed, “we could think more aggressively about how to harness that technology and apply it to the development of a therapy for macular degeneration in humans,” said Mark Petrash, an eye disease researcher at the University of Colorado and soon-to-be associate director of the Gates Center. The Gates donors would match funds raised by Naresh Mandava, an ophthalmology researcher and chair of the Department of Ophthalmology at the University of Colorado School of Medicine, to create an ocular stem cell program.

The cells are actually talking to each other. They are a lot happier and healthier if you grow them together. 
– Valeria Canto-Soler, University of Colorado

Once they raised sufficient funds, Petrash and Mandava started a search for a director for their new program, and Petrash flew to Johns Hopkins University to interview Canto-Soler. “I made a trip up there to meet her to have dinner and explain what our vision was,” he said.

After they met, Canto-Soler said, “Their vision was almost like a mirror vision of mine.”

In July 2017, Canto-Soler moved to Colorado and launched CellSight, which is the University of Colorado Department of Ophthalmology’s Ocular Stem Cell and Regeneration Research Program. Canto-Soler wanted to bring together a team of people from several disciplines, including basic researchers through clinicians to work independently on their own projects, but also to come together to solve bigger problems, with the hope that someday they could cure blindness. The program recruited retinal researchers Joseph Brzezinski, Natalia Vergara, Miguel Flores-Bellver, and vitreoretinal surgeon Marc Mathias. A new lab facility was built, and the researchers started generating retinal organoids from iPS cells and finetuning their protocols.

An organoid takes as long to form in the lab as a retina takes to grow during normal human development in utero. When complete, each organoid is only one to two millimeters in diameter, and they grow better when they’re with other organoids. “The cells are actually talking to each other,” said Canto-Soler. “They are a lot happier and healthier if you grow them together.”

Although the cells that the researchers differentiated into retinal cells self-assembled into 3D structures containing most layers of the retina, one vital layer, the retinal pigment epithelium (RPE), required additional tweaking. When it was grown from iPS cells, it didn’t position itself correctly relative to the photoreceptors, so Flores-Bellver developed a new protocol to grow a functional RPE monolayer, and then the team built a 3D complex with the RPE correctly positioned facing the photoreceptors and the rest of the retinal organoid layers. Concurrently, Brzezinski investigated how the retina develops embryonically. He has also researched the developmental mechanisms that lead to the many retinal cell types forming at the right time, proportion, and place.

Layers of glial cells, neurons, and membranes form the human retina.

credit: iStock.com/Sinhyu

“[Now, retinal organoids] are at a stage where they have begun to be common practice in our field. Many labs are routinely using them for disease modeling,” said Kapil Bharti, an ocular and stem cell researcher at the National Eye Institute, who is not involved with CellSight. 

In 2023, Johns Hopkins University, China Medical University, and University of Maryland researchers used CellSight retinal organoids as one of several models to study how oxidative stress affects retinas (3). “We used them as a tool, a very helpful tool, but in conjunction with human tissue, animal models, and cell-based models,” said Akrit Sodhi, the retinal researcher at Johns Hopkins University who conducted this study. “No one tool, the organoids included, is a perfect tool. It’s very effective in filling in some of the gaps in our understanding using other models.”

Researchers in Vergara’s group also created retinal organoids from patients with familial forms of Alzheimer’s disease using cells that contained mutations in the amyloid precursor protein gene. They found that organoids made from these patient samples resembled healthy organoids but also accumulated more Aβ and pTau, the main hallmarks of Alzheimer’s disease (4). 

Sodhi said that retinal organoids work well as disease models because researchers can manipulate them. But there are also disadvantages. The organoids are immature and have no vasculature, which could be a problem since most retinal diseases involve alterations to blood vessels. In addition, all the pertinent cells may not be present. Some cells die early because certain synapses don’t form, while other cells develop later. “You reproduce a lot of what’s missing in, say, cell culture or animal models,” said Sodhi. “It’s not a perfect model, but it’s definitely a huge step forward.”

CellSight uses retinal organoids to screen drugs, especially those that may prevent photoreceptor loss in retinal degenerative diseases. Vergara will use her Alzheimer’s disease retinal organoid model to evaluate drug candidates. She is also collaborating with researchers at Boston Children’s Hospital to help a patient with a rare mutation that leads to untreatable photoreceptor degeneration. The group developed an antisense oligonucleotide therapy to fix the mutation in the patient’s RNA so the protein is produced normally, and Vergara’s group is making retinal organoids using the patient’s own cells to see if the experimental treatment will work. 

Vergara is optimistic that the approach will give the patient’s doctors valuable knowledge about treatment efficacy. “We are very excited because it will help us establish a pipeline for the potential treatment of other rare blinding diseases,” she wrote in an email. “There’s currently no cure for these diseases, and because they are rare, there’s little incentive for big companies to develop innovative treatments.” 

Retinal organoid transplants?

In addition to disease models and drug screening, the other long-term goal for retinal organoid research is developing retinal transplants for people who have severe retinal degeneration and have lost their sight. “We dream of developing a transplant program to try to give vision back to these patients,” Vergara said.

Other researchers have begun to study transplanting just the 2D RPE layer of the retina into patients. These patients have early-stage disease, and their retinas are mostly functional. Later stage disease, in which more cells have degenerated and sight is lost, would require a larger transplantation of all the retinal layers. At this stage, the researchers hope to transplant a retinal organoid plus the RPE. 

We dream of developing a transplant program to try to give vision back to these patients. 
– Natalia Vergara, University of Colorado

Mathias is testing retinal transplants generated from retinal organoids in pigs since their eyes are similar to human eyes. Mathias, his colleagues at Johns Hopkins University, and the CellSight team have created a surgical kit for delivering their retinal transplants into pigs by working with a medical device company to create the tools necessary; they have completed proof of concept studies and hope that these surgical techniques can be translated into humans (5). 

“We have this amazing ability to grow mini-retinas, or retinal organoids in the lab, that mimic the retina in the eye,” said Mathias. “The challenge is getting those into the tissue where it needs to heal a disease process and integrate with the remaining cells that are healthy … [and] are connected back to the brain.” He hopes that it will be possible to test such a transplant in humans within the next six years.

There are many challenges ahead. Experts caution that the transplants derived from retinal organoids must survive within the host retina after transplantation and adapt to the vascular network, while neurons will have to establish synapses and communicate with each other and also with the optic nerve and the brain. The transplants also need to survive the potentially unhealthy retinal environment in which the previous retinal cells died. This is a complex undertaking, and some experts caution that retinal organ transplantation could be many, many years away.

Canto-Soler is grateful for the opportunity, no matter how long it takes. “It was like a magic moment! When you have a vision, you don’t know how you are going to bring it to life, and someone knocks on your door and says, ‘Hey, we have the same vision. We have what you need, and would you like to work with us?’” said Canto-Soler. “Our hope is over the next five years or so, we may be able to demonstrate that it’s a safe procedure that has potential for benefiting patients and eventually being able to reach clinical trial to test in patients. That’s still a long way ahead.” 

References

  1. Takahashi, K. and Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell  126, 663-676 (2006).
  2. Zhong, X. et al. Generation of three-dimensional retinal tissue with functional photoreceptors from human iPSCs. Nat Commun  5, 4047 (2014).
  3. Babapoor-Farrokhran, S. et al.Pathologic vs. protective roles of hypoxia-inducible factor 1 in RPE and photoreceptors in wet vs. dry age-related macular degeneration. PNAS  120, e2302845120 (2023).
  4. James, E. et al. Human iPSC-derived retinal organoids develop robust Alzheimer’s disease neuropathology. Front Cell Neurosci  18, 1340448 (2024).
  5. Li, K.V. et al. A surgical kit for stem cell-derived retinal pigment epithelium transplants: Collection, transportation, and subretinal delivery.Front Cell Dev Biol  10, 813538 (2022).

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diabetic retinopathy, and retinitis pigmentosa are more common, yet physicians have little to offer patients who have lost their rods, cones, and other retinal cells. 

Back in 2006, Valeria Canto-Soler, then an eye researcher at Johns Hopkins University, used animal models and cell cultures to investigate the retina, but these models were disappointingly inadequate. Two-dimensional cell cultures could not approximate intricate 3D retinas packed with layers of discrete cell types living in a rich physical environment, and animal models did not accurately represent retinal anatomy and human disease pathogenesis.

Then, unexpectedly, there was “a revolution in the field,” said Canto-Soler. Cell biologists Kazutoshi Takahashi and Shinya Yamanaka at Kyoto University introduced four factors into mammalian cells and turned back time, reversing differentiation and allowing adult fibroblasts to become any cell in the body. They called these induced pluripotent stem (iPS) cells (1). “That’s the time when I started to think about the possibility of using human iPS cells to generate a 3D tissue that would resemble as close as possible the retinal tissue,” said Canto-Soler.

Motivated by the lack of adequate treatment options for patients with retinal degenerative diseases, Canto-Soler started her own research group at Johns Hopkins University to try to address this unmet need. She and her team got to work using iPS cells to generate 3D retinal tissues. They studied and manipulated iPS cells for years, while other research groups made strides with embryonic stem cells. 

Canto-Soler’s group kept pushing. Finally, they hit the jackpot: In 2014, they published the first paper showing that iPS cells could self-assemble into a 3D retinal organoid with all the cell layers in the right order and photoreceptors sensitive to light (2). 

“That’s the time when I started to envision a bigger program, not just my lab,” she said. “A team of investigators that would have complementary expertise, that will know the things that I didn’t know… Can we translate these into retinal transplants to restore vision in patients who are blind because they have lost their photoreceptors?” 

Building the team: disease models and drug screening

At the same time as Canto-Soler worked on her iPS cell research, a philanthropic family led by Diane Gates Wallach and her brother John Gates, committed to fund new research in regenerative medicine, with a special interest in age-related macular degeneration (AMD). The family patriarch and former CEO of the Gates Rubber Company, Charles Gates Jr., had suffered from AMD and blindness at the end of his life, so they developed the Gates Center for Regenerative Medicine at the University of Colorado. 

Once the technology for easily creating iPS cells was developed, “we could think more aggressively about how to harness that technology and apply it to the development of a therapy for macular degeneration in humans,” said Mark Petrash, an eye disease researcher at the University of Colorado and soon-to-be associate director of the Gates Center. The Gates donors would match funds raised by Naresh Mandava, an ophthalmology researcher and chair of the Department of Ophthalmology at the University of Colorado School of Medicine, to create an ocular stem cell program.

The cells are actually talking to each other. They are a lot happier and healthier if you grow them together. 
– Valeria Canto-Soler, University of Colorado

Once they raised sufficient funds, Petrash and Mandava started a search for a director for their new program, and Petrash flew to Johns Hopkins University to interview Canto-Soler. “I made a trip up there to meet her to have dinner and explain what our vision was,” he said.

After they met, Canto-Soler said, “Their vision was almost like a mirror vision of mine.”

In July 2017, Canto-Soler moved to Colorado and launched CellSight, which is the University of Colorado Department of Ophthalmology’s Ocular Stem Cell and Regeneration Research Program. Canto-Soler wanted to bring together a team of people from several disciplines, including basic researchers through clinicians to work independently on their own projects, but also to come together to solve bigger problems, with the hope that someday they could cure blindness. The program recruited retinal researchers Joseph Brzezinski, Natalia Vergara, Miguel Flores-Bellver, and vitreoretinal surgeon Marc Mathias. A new lab facility was built, and the researchers started generating retinal organoids from iPS cells and finetuning their protocols.

An organoid takes as long to form in the lab as a retina takes to grow during normal human development in utero. When complete, each organoid is only one to two millimeters in diameter, and they grow better when they’re with other organoids. “The cells are actually talking to each other,” said Canto-Soler. “They are a lot happier and healthier if you grow them together.”

Although the cells that the researchers differentiated into retinal cells self-assembled into 3D structures containing most layers of the retina, one vital layer, the retinal pigment epithelium (RPE), required additional tweaking. When it was grown from iPS cells, it didn’t position itself correctly relative to the photoreceptors, so Flores-Bellver developed a new protocol to grow a functional RPE monolayer, and then the team built a 3D complex with the RPE correctly positioned facing the photoreceptors and the rest of the retinal organoid layers. Concurrently, Brzezinski investigated how the retina develops embryonically. He has also researched the developmental mechanisms that lead to the many retinal cell types forming at the right time, proportion, and place.

A microscope image of the human retina and the cells in different layers.

Layers of glial cells, neurons, and membranes form the human retina.

credit: iStock.com/Sinhyu

“[Now, retinal organoids] are at a stage where they have begun to be common practice in our field. Many labs are routinely using them for disease modeling,” said Kapil Bharti, an ocular and stem cell researcher at the National Eye Institute, who is not involved with CellSight. 

In 2023, Johns Hopkins University, China Medical University, and University of Maryland researchers used CellSight retinal organoids as one of several models to study how oxidative stress affects retinas (3). “We used them as a tool, a very helpful tool, but in conjunction with human tissue, animal models, and cell-based models,” said Akrit Sodhi, the retinal researcher at Johns Hopkins University who conducted this study. “No one tool, the organoids included, is a perfect tool. It’s very effective in filling in some of the gaps in our understanding using other models.”

Researchers in Vergara’s group also created retinal organoids from patients with familial forms of Alzheimer’s disease using cells that contained mutations in the amyloid precursor protein gene. They found that organoids made from these patient samples resembled healthy organoids but also accumulated more Aβ and pTau, the main hallmarks of Alzheimer’s disease (4). 

Sodhi said that retinal organoids work well as disease models because researchers can manipulate them. But there are also disadvantages. The organoids are immature and have no vasculature, which could be a problem since most retinal diseases involve alterations to blood vessels. In addition, all the pertinent cells may not be present. Some cells die early because certain synapses don’t form, while other cells develop later. “You reproduce a lot of what’s missing in, say, cell culture or animal models,” said Sodhi. “It’s not a perfect model, but it’s definitely a huge step forward.”

CellSight uses retinal organoids to screen drugs, especially those that may prevent photoreceptor loss in retinal degenerative diseases. Vergara will use her Alzheimer’s disease retinal organoid model to evaluate drug candidates. She is also collaborating with researchers at Boston Children’s Hospital to help a patient with a rare mutation that leads to untreatable photoreceptor degeneration. The group developed an antisense oligonucleotide therapy to fix the mutation in the patient’s RNA so the protein is produced normally, and Vergara’s group is making retinal organoids using the patient’s own cells to see if the experimental treatment will work. 

Vergara is optimistic that the approach will give the patient’s doctors valuable knowledge about treatment efficacy. “We are very excited because it will help us establish a pipeline for the potential treatment of other rare blinding diseases,” she wrote in an email. “There’s currently no cure for these diseases, and because they are rare, there’s little incentive for big companies to develop innovative treatments.” 

Retinal organoid transplants?

In addition to disease models and drug screening, the other long-term goal for retinal organoid research is developing retinal transplants for people who have severe retinal degeneration and have lost their sight. “We dream of developing a transplant program to try to give vision back to these patients,” Vergara said.

Other researchers have begun to study transplanting just the 2D RPE layer of the retina into patients. These patients have early-stage disease, and their retinas are mostly functional. Later stage disease, in which more cells have degenerated and sight is lost, would require a larger transplantation of all the retinal layers. At this stage, the researchers hope to transplant a retinal organoid plus the RPE. 

We dream of developing a transplant program to try to give vision back to these patients. 
– Natalia Vergara, University of Colorado

Mathias is testing retinal transplants generated from retinal organoids in pigs since their eyes are similar to human eyes. Mathias, his colleagues at Johns Hopkins University, and the CellSight team have created a surgical kit for delivering their retinal transplants into pigs by working with a medical device company to create the tools necessary; they have completed proof of concept studies and hope that these surgical techniques can be translated into humans (5). 

“We have this amazing ability to grow mini-retinas, or retinal organoids in the lab, that mimic the retina in the eye,” said Mathias. “The challenge is getting those into the tissue where it needs to heal a disease process and integrate with the remaining cells that are healthy … [and] are connected back to the brain.” He hopes that it will be possible to test such a transplant in humans within the next six years.

There are many challenges ahead. Experts caution that the transplants derived from retinal organoids must survive within the host retina after transplantation and adapt to the vascular network, while neurons will have to establish synapses and communicate with each other and also with the optic nerve and the brain. The transplants also need to survive the potentially unhealthy retinal environment in which the previous retinal cells died. This is a complex undertaking, and some experts caution that retinal organ transplantation could be many, many years away.

Canto-Soler is grateful for the opportunity, no matter how long it takes. “It was like a magic moment! When you have a vision, you don’t know how you are going to bring it to life, and someone knocks on your door and says, ‘Hey, we have the same vision. We have what you need, and would you like to work with us?’” said Canto-Soler. “Our hope is over the next five years or so, we may be able to demonstrate that it’s a safe procedure that has potential for benefiting patients and eventually being able to reach clinical trial to test in patients. That’s still a long way ahead.” 

References

  1. Takahashi, K. and Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell  126, 663-676 (2006).
  2. Zhong, X. et al. Generation of three-dimensional retinal tissue with functional photoreceptors from human iPSCs. Nat Commun  5, 4047 (2014).
  3. Babapoor-Farrokhran, S. et al.Pathologic vs. protective roles of hypoxia-inducible factor 1 in RPE and photoreceptors in wet vs. dry age-related macular degeneration. PNAS  120, e2302845120 (2023).
  4. James, E. et al. Human iPSC-derived retinal organoids develop robust Alzheimer’s disease neuropathology. Front Cell Neurosci  18, 1340448 (2024).
  5. Li, K.V. et al. A surgical kit for stem cell-derived retinal pigment epithelium transplants: Collection, transportation, and subretinal delivery.Front Cell Dev Biol  10, 813538 (2022).

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