Animal models in biomedical research help scientists see what works, what doesn’t and why. Two research projects—one at the University of Wisconsin–Madison’s McPherson Eye Research Institute and the Morgridge Research Institute, and the other at the National Eye Institute (NEI) at the National Institutes of Health (NIH)—utilized animal models in vision research. What they discovered could advance eye treatments and lead to better outcomes for people with eye diseases.
Pig Cells to the Rescue
Using stem cell replacement therapy with lab-grown photoreceptors is one way to tackle retinal disease. However, treatments using stem cells to replace photoreceptors need to be tested in animals—and human cells aren’t compatible with other species, so they’re quickly rejected.
That means a viable animal model is needed. Scientists at the University of Wisconsin (UW) Madison’s McPherson Eye Research Institute and the Morgridge Research Institute used pig retinas. In a study that was published in Stem Cell Reports, the lab of David Gamm, MD, PhD at the UW McPherson Eye Research Institute—working with scientists at Morgridge—discovered that pig-derived photoreceptors retinas share many features with those made from human retinal organoids. This study marks the first time people made pig retinal organoids and compared them to human retinal organoids.
Once the pig stem cells were generated, the next step was to develop them into retinal cells. The scientists at Morgridge used Gamm lab’s human organoid protocol to see if it would work with pig stem cells. The original protocol time was based on human gestation of 40 weeks. Since a pig’s gestation period is half that time, the Morgridge scientists halved the protocol duration—and it worked. Scientists have started doing transplants in pigs using the lab grown photoreceptors to see if they work properly in a living organism.
“We’re excited to show that you can grow these retinal organoids from different species and that a lot of groups across the world are starting to make them,” says Kim Edwards, a graduate student in the Gamm Lab and first author of the study. “It all starts from having good stem cells.”
Slowing Retinal Disease, One Drop at a Time
While using stems cells to cure retinal disease sounds promising, it is labor intensive and very complex. Is there a simpler treatment in development? Research in the lab of Patricia Becerra, Ph.D., chief of National Institutes of Health (NIH)’s Section on Protein Structure and Function at the National Eye Institute and senior author of the study, led to the development of eye drops that extend useful vision in animal models of retinal disease.
The eye drops have a small particle originating from a protein found in the eye, known as pigment epithelium-derived factor (PEDF). This protein helps preserve cells in the retina. While these drops aren’t a cure for retinal diseases, research shows that that PEDF-based eye drops can slow progression of various eye diseases, such as retinitis pigmentosa and dry age-related macular degeneration.
What all degenerative retinal diseases have in common is cellular stress. High levels of stress cause retinal cells to slowly lose function and die.It is the loss of retinal cells, like photoreceptor cells, which lead to vision loss and eventually blindness.
Previous research in Becerra’s lab showed that PEDF could help delay the effects of cellular stress in a mouse model. The problem is that the PEDF protein is too large to pass through the eye tissue to reach the retina. So, to enhance the molecule’s ability to reach the back of the eye and preserve retinal cells, Becerra’s lab created a group of short peptides derived from a part of PEDF that supports cell viability. These peptides can penetrate eye tissue and bind with PEDF receptor proteins on the retina’s surface.
In this new study, scientists in Becerra’s lab made two eye drop formulations, each containing a short peptide. One formulation has a peptide called 17-mer, which has 17 amino acids found in PEDF’s active region. The other formulation has a peptide called H105A. This is similar to 17-mer but binds more strongly to the PEDF receptor. These were peptides applied as drops to the surface of a mouse’s eye, and neither peptide had harmful side effects.
To test the effectiveness of the drops, researchers used a type of mice that were bred to lose their photoreceptors shortly after birth. When treated with the eye drops, the mice kept up to 75 percent of their photoreceptors and continued to respond strongly to light. Since gene-specific therapies for retinitis pigmentosa are still in development, these eye drops could play an important role in preserving cells in the meantime.
To determine if photoreceptors preserved with the eye drops are healthy enough for gene therapy, collaborators at the University of Modena treated mice with gene therapy at the end of a week-long eye drop program. This proved successful and the mice’s vision were preserved for six months.
Could this work in humans? To find out without testing on humans directly, scientists at the University of Colorado Anschutz tested the peptides in a human retinal tissue model of retinal degeneration. These were lab grown human retinal cells exposed to chemicals that caused a high level of cellular stress. Without the peptides the cells in the tissue model died. With the peptides, the cells remained viable. This data provides important support for future human trials of these eye drops.
From pig cells to eye drops, there’s no shortage of tools that scientists are exploring to improve vision treatment. These two studies reveal what works—and what doesn’t. Researchers at University of Wisconsin showed that it is possible to use organoids from another species. Meanwhile, NIH scientists proved that PEDF supports retinal cell health. Together, these projects show how innovation and perseverance can lead to better treatments for vision diseases.