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Moving Closer to a Stem Cell-Based Treatment for AMD

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In recent years, researchers have figured out how to take a person’s skin or blood cells and turn them into induced pluripotent stem cells (iPSCs) that offer tremendous potential for regenerative medicine. Still, it’s been a challenge to devise safe and effective ways to move this discovery from the lab into the clinic. That’s why I’m pleased to highlight progress toward using iPSC technology to treat a major cause of vision loss: age-related macular degeneration (AMD).

In the new work, researchers from NIH’s National Eye Institute developed iPSCs from blood-forming stem cells isolated from blood donated by people with advanced AMD [1]. Next, these iPSCs were exposed to a variety of growth factors and placed on supportive scaffold that encouraged them to develop into healthy retinal pigment epithelium (RPE) tissue, which nurtures the light-sensing cells in the eye’s retina. The researchers went on to show that their lab-grown RPE patch could be transplanted safely into animal models of AMD, preventing blindness in the animals.

This preclinical work will now serve as the foundation for a safety trial of iPSC-derived RPE transplants in 12 human volunteers who have already suffered vision loss due to the more common “dry” form of AMD, for which there is currently no approved treatment. If all goes well, the NIH-led trial may begin enrolling patients as soon as this year.

Risk factors for AMD include a combination of genetic and environmental factors, including age and smoking. Currently, more than 2 million Americans have vision-threatening AMD, with millions more having early signs of the disease [2].

AMD involves progressive damage to the macula, an area of the retina about the size of a pinhead, made up of millions of light-sensing cells that generate our sharp, central vision. Though the exact causes of AMD are unknown, RPE cells early on become inflamed and lose their ability to clear away debris from the retina. This leads to more inflammation and progressive cell death.

As RPE cells are lost during the “dry” phase of the disease, light-sensing cells in the macula also start to die and reduce central vision. In some people, abnormal, leaky blood vessels will form near the macula, called “wet” AMD, spilling fluid and blood under the retina and causing significant vision loss. “Wet” AMD has approved treatments. “Dry” AMD does not.

But, advances in iPSC technology have brought hope that it might one day be possible to shore up degenerating RPE in those with dry AMD, halting the death of light-sensing cells and vision loss. In fact, preliminary studies conducted in Japan explored ways to deliver replacement RPE to the retina [3]. Though progress was made, those studies highlighted the need for more reliable ways to produce replacement RPE from a patient’s own cells. The Japanese program also raised concerns that iPSCs derived from people with AMD might be prone to cancer-causing genomic changes.

With these challenges in mind, the NEI team led by Kapil Bharti and Ruchi Sharma have designed a more robust process to produce RPE tissue suitable for testing in people. As described in Science Translational Medicine, they’ve come up with a three-step process.

Rather than using fibroblast cells from skin as others had done, Bharti and Sharma’s team started with blood-forming stem cells from three AMD patients. They reprogrammed those cells into “banks” of iPSCs containing multiple different clones, carefully screening them to ensure that they were free of potentially cancer-causing changes.

Next, those iPSCs were exposed to a special blend of growth factors to transform them into RPE tissue. That recipe has been pursued by other groups for a while, but needed to be particularly precise for this human application. In order for the tissue to function properly in the retina, the cells must assemble into a uniform sheet, just one-cell thick, and align facing in the same direction.

So, the researchers developed a specially designed scaffold made of biodegradable polymer nanofibers. That scaffold helps to ensure that the cells orient themselves correctly, while also lending strength for surgical transplantation. By spreading a single layer of iPSC-derived RPE progenitors onto their scaffolds and treating it with just the right growth factors, the researchers showed they could produce an RPE patch ready for the clinic in about 10 weeks.

To test the viability of the RPE patch, the researchers first transplanted a tiny version (containing about 2,500 RPE cells) into the eyes of a rat with a compromised immune system, which enables human cells to survive. By 10 weeks after surgery, the human replacement tissue had integrated into the animals’ retinas with no signs of toxicity.

Next, the researchers tested a larger RPE patch (containing 70,000 cells) in pigs with an AMD-like condition. This patch is the same size the researchers ultimately would expect to use in people. Ten weeks after surgery, the RPE patch had integrated into the animals’ eyes, where it protected the light-sensing cells that are so critical for vision, preventing blindness.

These results provide encouraging evidence that the iPSC approach to treating dry AMD should be both safe and effective. But only a well-designed human clinical trial, with all the appropriate prior oversights to be sure the benefits justify the risks, will prove whether or not this bold approach might be the solution to blindness faced by millions of people in the future.

As the U.S. population ages, the number of people with advanced AMD is expected to rise. With continued progress in treatment and prevention, including iPSC technology and many other promising approaches, the hope is that more people with AMD will retain healthy vision for a lifetime.

References:

[1] Clinical-grade stem cell-derived retinal pigment epithelium patch rescues retinal degeneration in rodents and pigs. Sharma R, Khristov V, Rising A, Jha BS, Dejene R, Hotaling N, Li Y, Stoddard J, Stankewicz C, Wan Q, Zhang C, Campos MM, Miyagishima KJ, McGaughey D, Villasmil R, Mattapallil M, Stanzel B, Qian H, Wong W, Chase L, Charles S, McGill T, Miller S, Maminishkis A, Amaral J, Bharti K. Sci Transl Med. 2019 Jan 16;11(475).

[2] Age-Related Macular Degeneration, National Eye Institute.

[3] Autologous Induced Stem-Cell-Derived Retinal Cells for Macular Degeneration. Mandai M, Watanabe A, Kurimoto Y, Hirami Y, Takasu N, Ogawa S, Yamanaka S, Takahashi M, et al. N Engl J Med. 2017 Mar 16;376(11):1038-1046.

Links:

Facts About Age-Related Macular Degeneration (National Eye Institute/NIH)

Stem Cell-Based Treatment Used to Prevent Blindness in Animal Models of Retinal Degeneration (National Eye Institute/NIH)

Kapil Bharti (NEI)

NIH Support: National Eye Institute; Common Fund


Regenerative Medicine: The Promise and Peril

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Retinal pigment epithelial cells

Caption: Scanning electron micrograph of iPSC-derived retinal pigment epithelial cells growing on a nanofiber scaffold (blue).
Credit: Sheldon Miller, Arvydas Maminishkis, Robert Fariss, and Kapil Bharti, National Eye Institute/NIH

Stem cells derived from a person’s own body have the potential to replace tissue damaged by a wide array of diseases. Now, two reports published in the New England Journal of Medicine highlight the promise—and the peril—of this rapidly advancing area of regenerative medicine. Both groups took aim at the same disorder: age-related macular degeneration (AMD), a common, progressive form of vision loss. Unfortunately for several patients, the results couldn’t have been more different.

In the first case, researchers in Japan took cells from the skin of a female volunteer with AMD and used them to create induced pluripotent stem cells (iPSCs) in the lab. Those iPSCs were coaxed into differentiating into cells that closely resemble those found near the macula, a tiny area in the center of the eye’s retina that is damaged in AMD. The lab-grown tissue, made of retinal pigment epithelial cells, was then transplanted into one of the woman’s eyes. While there was hope that there might be actual visual improvement, the main goal of this first in human clinical research project was to assess safety. The patient’s vision remained stable in the treated eye, no adverse events occurred, and the transplanted cells remained viable for more than a year.

Exciting stuff, but, as the second report shows, it is imperative that all human tests of regenerative approaches be designed and carried out with the utmost care and scientific rigor. In that instance, three elderly women with AMD each paid $5,000 to a Florida clinic to be injected in both eyes with a slurry of cells, including stem cells isolated from their own abdominal fat. The sad result? All of the women suffered severe and irreversible vision loss that left them legally or, in one case, completely blind.


Snapshots of Life: Lighting up the Promise of Retinal Gene Therapy

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mouse retina

Caption: Large-scale mosaic confocal micrograph showing expression of a marker gene (yellow) transferred by gene therapy techniques into the ganglion cells (blue) of a mouse retina.
Credit: Keunyoung Kim, Wonkyu Ju, and Mark Ellisman, National Center for Microscopy and Imaging Research, University of California, San Diego

The retina, like this one from a mouse that is flattened out and captured in a beautiful image, is a thin tissue that lines the back of the eye. Although only about the size of a postage stamp, the retina contains more than 100 distinct cell types that are organized into multiple information-processing layers. These layers work together to absorb light and translate it into electrical signals that stream via the optic nerve to the brain.

In people with inherited disorders in which the retina degenerates, an altered gene somewhere within this nexus of cells progressively robs them of their sight. This has led to a number of human clinical trials—with some encouraging progress being reported for at least one condition, Leber congenital amaurosis—that are transferring a normal version of the affected gene into retinal cells in hopes of restoring lost vision.

To better understand and improve this potential therapeutic strategy, researchers are gauging the efficiency of gene transfer into the retina via an imaging technique called large-scale mosaic confocal microscopy, which computationally assembles many small, high-resolution images in a way similar to Google Earth. In the example you see above, NIH-supported researchers Wonkyu Ju, Mark Ellisman, and their colleagues at the University of California, San Diego, engineered adeno-associated virus serotype 2 (AAV2) to deliver a dummy gene tagged with a fluorescent marker (yellow) into the ganglion cells (blue) of a mouse retina. Two months after AAV-mediated gene delivery, yellow had overlaid most of the blue, indicating the dummy gene had been selectively transferred into retinal ganglion cells at a high rate of efficiency [1].


Snapshots of Life: Seeing, from Eye to Brain

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Credit: Xueting Luo and Kevin Park, University of Miami

Fasten your seat belts! We’re going to fly through the brain of a mouse. Our tour guide is Kevin Park, an NIH-funded neuroscientist at the University of Miami, who has developed a unique method to visualize neurons in an intact brain. He’s going to give us a rare close-up of the retinal ganglion cells that carry information from the eye to the brain, where the light signals are decoded and translated.

To make this movie, Park has injected a fluorescent dye into the mouse eye; it is taken up by the retinal cells and traces out the nerve pathways from the optic nerve into the brain.


Meet Alex—Before and After NIH Clinical Trial

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Photo of an infant with mottled skin adjacent to a photo of young man with clear skin being examined by a female doctor.

Caption: Alex, then and now, with Dr. Goldbach-Mansky
Credit: Kate Barton and Susan Bettendorf (NIH)

Alex Barton recently turned 17. That’s incredible because Alex was born with a rare, often fatal genetic disease and wasn’t expected to reach his teenage years.

When Alex was born, he looked like he’d been dipped in boiling water: his skin was bright red and blistered. He spent most of his time sleeping. When awake, he screamed in agony from headaches, joint pain, and rashes. After a torturous 14 months, a rheumatologist told his mother that Alex suffered from Neonatal-Onset Multisystem Inflammatory Disease (NOMID). The doctor showed her a brief and scary paragraph in a medical text. Kate Barton, Alex’s mother, admitted that it “knocked her over like a freight train.”


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