February 2019

RETINA

Research highlight
Stem cell status


by Maxine Lipner EyeWorld Senior Contributing Writer




De novo genesis of rod photoreceptors in the eye
Source: Bo Chen, PhD

 

Retinal regeneration making inroads

When it comes to retinal stem cell regeneration for conditions such as age-related macular degeneration and retinitis pigmentosa, a variety of different approaches have been tried, according to Petr Baranov, MD, assistant scientist, Schepens Eye Research Institute of Massachusetts Eye and Ear, Boston. “In terms of transplantation cell replacements, it’s interesting how the whole field has been developing for the last 3 decades,” Dr. Baranov said. In a review published in Therapeutic Advances in Ophthalmology,1 Dr. Baranov took a closer look at current approaches to handling the fact that cells on the human retina do not regenerate on their own.
The goal is to find a way to properly replace lost cells. “We want to make a cell that would mimic a retinal cell as closely as possible,” Dr. Baranov said. “Then we would deliver it into a recipient environment, and the cell that we would deliver would integrate properly and become a real cell.”

Techniques

One approach deals with taking retinal progenitor cells and expanding them in incubators. The idea is to then inject the cells back into the eye and have them function, Dr. Baranov explained. “We found at least two trials [in the literature] and both used cells delivered as suspension,” Dr. Baranov said, adding that this suspension was injected into the subretinal space.
There is also now a second generation strategy using pluripotent or induced pluripotent stem cells taken from other areas such as the skin and coaxed back into the embryonic state, then getting them to differentiate into retinal pigment epithelium cells or neurons.
“This is a challenge because it’s hard to make something in vitro that would be the same as in vivo,” he said. He noted that with any of these approaches, a lot of cells die during the injection and some do not properly integrate into the retina, instead remaining in the intermediate space.
Some have also been looking into tissue engineering approaches. “That means that we would make an actual tissue-like structure where donor cells would already have contact with each other,” Dr. Baranov said. “They would already have a proper architecture.” With this type of approach, the delivery becomes more complicated since this is now real graft surgery, he explained; however, once you deliver those cells, since they already have proper tissue architecture, they already have context, making it easier for them to acquire proper function.
Dr. Baranov cited a trial led by Peter Coffey, PhD, on delivering retinal pigment epithelium (RPE) as a patch of cells. “We’ll see how it’s going to develop, but I think it’s a great example that it’s possible and that we could achieve good results,” Dr. Baranov said. With this approach, investigators were able to successfully deliver an RPE patch in two patients, which resulted in an improvement in best corrected visual acuity of up to 29 letters.2
Still, there are no side-by-side clinical studies showing that a tissue-like patch works better than a suspension of cells, Dr. Baranov stressed.

Reprogramming Muller glial cells

Bo Chen, PhD, associate professor, Icahn School of Medicine at Mount Sinai, New York, has been working on another strategy: attempting to activate the regenerative capability of the retina using Muller glial cells. In lower species such as zebra fish, Muller glial cells serve as stem cells in residence in addition to supporting retinal function, Dr. Chen explained. “Whenever there’s a loss of retinal neurons by injury or damage, these cells immediately move into the regenerative state and divide and make more retinal neurons,” he said, adding that unfortunately, Muller glial cells do not perform this regenerative function in mammals.
Dr. Chen and fellow investigators have been working to wake up the regenerative capacity of such cells. “Previous studies show Muller glial cells can be manipulated to have some features of retinal stem cells,” he said. “But these earlier studies used strategies such as neurotoxin-induced retinal injury to activate the stem cell state of the Muller glial cells in the mammalian retina.” However, such injuries almost completely kill retinal ganglion cells, the only output neuron of the retina.
Instead, his lab has used viruses to deliver genes directly into Muller glial cells to activate them without introducing any damage to the retina. The technique involves a two-step reprogramming process. “The first is by gene transfer to activate the Muller glial cells to stem cell state,” Dr. Chen said. “Following the first step, we reprogram by gene transfer of 3 factors important for photoreceptor differentiation during early retinal development.” After this, investigators found that the Muller glial cells give rise to rod photoreceptor cells that so far are indistinguishable from original rod photoreceptor cells.
What’s more, in the mouse model of congenital blindness, they showed that after reprogramming, newly generated rod photoreceptors were able to function.3 “They can respond to light, and they deliver information to retinal ganglion cells,” Dr. Chen said. “The newly gained visual information made their way all the way to the visual cortex, enabling the congenitally blind mice to respond to light for the first time in their lives.”
Once this technology is mature, Dr. Chen expects that it will be applicable for many forms of retinal degenerative diseases such as macular degeneration and retinitis pigmentosa.
Overall, Dr. Baranov thinks that there has been great success in cell transplantation and regenerative therapies in the eye already. “I think the eye is the place to be,” he said. “That’s where cell transplantation studies can progress faster than in other areas because we can monitor function, we can look into the eye, and we can have good structure readouts on cellular and even subcellular levels.”

References

1. Oswald J, Baranov P. Regenerative medicine in the retina: from stem cells to cell replacement therapy. Ther Adv Ophthalmol. 2018;10:2515841418774433.
2. da Cruz L, et al. Phase 1 clinical study of an embryonic stem cell-derived retinal pigment epithelium patch in age-related macular degeneration. Nat Biotechnol. 2018;36:328–337.
3. Yao K, et al. Restoration of vision after de novo genesis of rod photoreceptors in mammalian retinas. Nature. 2018;560:484–488.

Editors’ note: The sources have patents related to this.

Contact information

Baranov
: Petr_Baranov@MEEI.HARVARD.EDU
Chen: bo.chen@mssm.edu

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