Progress In The Search To Reverse Age-Related Vision Loss

Thanks to new techniques in regenerative medicine, we are closer to a future where your own cells can be used to restore vision. A recent publication by Ripolles-Garcia et al. at the University of Pennsylvania School of Veterinary Sciences describes a novel approach for both generating and surgically implanting such cells directly into affected areas of the retina.

Macular degeneration is one of the main causes of blindness. Over 15 million Americans over the age of 50 suffer from some form of age-related macular degeneration, a genetic disease characterized by loss of vision. The most common form, dry macular degeneration, develops as a result of widespread damage to photoreceptor cells in the central region of the retina, called the macula. As the site of greatest concentration of these light-sensitive cells, degeneration of photoreceptors in the macula gradually alters central vision and, in rare cases, can lead to complete blindness. Remarkably, studies show that the inner structure of the retina remains intact even when the photoreceptor cells degenerate with age.

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More than 270 genes have been linked to macular degeneration and other inherited retinal diseases. Additional environmental factors such as diet and smoking can also increase the risk of developing macular degeneration with age. However, despite the prevalence of age-related macular degeneration, there are no readily available treatments to restore vision.

The team at the UPenn School of Veterinary Science and related institutions has made significant strides in finding cures for macular degeneration and other causes of vision loss. Ripolles-Garcia et al. shows that retinal progenitor cells obtained from tiny samples of human pluripotent stem cells can effectively replace damaged photoreceptor cells. Further tweaking this technique to ensure integration with the rest of the retina could restore vision to millions of people.

Stem cells for regenerative retinal therapy

New techniques in regenerative medicine have made it possible to take small samples of your own cells and turn them back into stem cells, which can regenerate into almost any type of cell in the body. For retinal therapies, this means first creating pluripotent stem cells (iPS cells) and then applying cell-specific treatments that gently nudge them into becoming retinal progenitor cells. Ripolles-Garcia et al. injected these progenitor cells directly into the retina in their experiment with the aim of replacing damaged photoreceptors.

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However, there are major challenges in using stem cells for retinal regenerative therapy. First, to compensate for the widespread prevalence of damaged receptors, large amounts of retinal progenitor cells must be delivered directly to the subretinal space without damaging other structures in the eye. Second, ensuring the survival of these cells depends on avoiding activation of the innate immune system. Eventually, the cells must be able to make connections with the rest of the retina to restore vision.

This study uncovered an innovative approach to not only transplant stem cell-derived photoreceptor cells into the retina, but also to avoid immune rejection. Ripolles-Garcia et al. recruited dogs with retinal mutations similar to those associated with human retinal diseases and treated them with retinal progenitor cells derived from human pluripotent cells. This was followed by daily administration of immunosuppressants. These cells were remarkably capable of making meaningful connections with the rest of the eye, leaving one question unanswered: “Can retinal transplants actually restore vision?”

delivery

The first challenge this study faced was to safely deliver a significant amount of photoreceptor progenitor cells to the subretinal space. In order for a wide cannula to reach the back of the retina, part of the vitreous humor, the gel-like substance between the lens and the retina, usually has to be removed. However, dislodging the vitreous gel can cause newly injected retinal cells to flow back into the rest of the eye, further obstructing vision. Instead, Ripolles-Garcia et al. designed a smaller cannula that injected cells directly into the back of the retina without removing the vitreous layer.

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The retinal stem cell progenitors used in this procedure were labeled with a fluorescent dye before being injected into the retina, allowing researchers to track their position and distribution over time using non-invasive imaging. In one of their first observations, imaging showed that gravitational effects contributed to an uneven distribution of cells across the retina. The researchers argued that these effects could be mitigated in clinical settings by allowing subjects to lie horizontally in the days following the procedure.

Avoid immune rejection

A total of seven healthy dogs and three dogs with retinal mutations were divided into two groups: those who received a triple cocktail of anti-inflammatory immunosuppressive drugs continuously after transplantation and those who received no drugs at all. Blood and urine samples collected during the evaluation period confirmed that this highly immunosuppressive treatment was well tolerated in this experimental group.

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In both groups, Ripolles-Garcia et al. observed an initial loss of transplanted photoreceptor cells in the first few days after injection. However, the animals not receiving the immunosuppressive regimen experienced continued loss of these cells until the fluorescently labeled retinal progenitor cells were undetectable. In addition, the researchers found that both normal and mutant dogs in this group showed evidence of a robust innate immune response, given by the increased presence of macrophages and activated microglia in the capillaries surrounding the retina. This robust immune response, along with the complete loss of stem cell-derived photoreceptors, in dogs that have not received anti-inflammatory drugs suggests that immunosuppression is critical to avoiding immune rejection and prolonging the survival of transplanted cells.

integration

For the final challenge in this study, the researchers had to ensure that the photoreceptor cells that survived the transplant could integrate into the retina to restore vision. Within the group receiving the immunosuppressive regimen, the normal dogs had smaller fluorescently labeled clusters unaccompanied by an inflammatory response over time. In contrast, the clusters of the transplanted cells in the dogs with retinal mutations remained unchanged. It is likely that the donated cells filled in the gaps left by degenerated photoreceptors, requiring less remodeling of retinal architecture.

As William Beltran, one of the senior authors of this study and a professor of ophthalmology at Penn Vet, says, “What we showed was that if you inject the cells into a normal retina with its own photoreceptor cells, the retina is pretty much intact and serves as a physical barrier to keep the introduced cells from connecting to the second-order neurons in the retina, called bipolar cells. But in three dogs with advanced stages of retinal degeneration, the retinal barrier was more permeable. In this environment, the cells had a better ability to move to the correct layer of the retina.” The donated cells, which make connections to internal structures of the retina, are then in a perfect position to send visual information to the brain.

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Conclusion

This approach is still a long way from being used to treat retinal degeneration in humans. For one, the level of immunosuppression required to support these cells may not be practical in humans, let alone safe. The dogs recruited for this study received immunosuppressive drugs for the duration of the study until they were euthanized at the end. It’s unclear how long a person would need to be on an immunosuppressive regimen to avoid immune rejection. Also, given the nature of using animal subjects, we still don’t know if donating new cells will restore vision. This is potentially a question that can only be answered through clinical trials.

A regenerative therapy that replaces damaged photoreceptors with retinal precursor stem cells could one day restore sight to millions of people. This study has set the stage to further optimize not only the delivery of these cells but also their long-term survival in future clinical trials.

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