Induced pluripotent stem cells (iPSC) — stem cells derived by genetically tweaking a small sample of a person’s skin or blood — are again demonstrating their power for helping researchers fight retinal diseases.
In this latest development, Stephen Tsang, M.D., Ph.D., a Foundation-funded researcher at Columbia University, used them to create a human model of age-related macular degeneration (AMD). The advancement not only gives us a better understanding of how AMD occurs; it provides a new, and potentially better, platform for testing vision-saving therapies. Results of the study were published in Human Molecular Genetics.
While it is the leading cause of blindness in people over 55 in developed countries, AMD has traditionally been a difficult disease to model for two primary reasons.
First, AMD is a complex retinal degenerative disease. There are several factors that can contribute to its development, including aging, genetic variations, environmental insults (e.g., excessive light exposure) and lifestyle habits (e.g., unhealthy diet, smoking).
Second, one of the commonly used tools for studying retinal diseases — rodents — don’t have a macula, the cone-rich central area of the retina, which enables humans to read, drive and recognize faces. While researchers have been able to model the biochemical process that leads to vision-robbing waste accumulation in AMD, the rodents’ lack of a macula has limited what can be learned.
Dr. Tsang created a human model of AMD by taking skin cells from two people at high risk for AMD due to variations in the genes ARMS2 and HTRA1 and reprogramming them to become iPSC. He then coaxed the iPSC into becoming retinal pigment epithelial (RPE) cells, which provide critical support to photoreceptors, but are significantly damaged in AMD. He also used the same process to create RPE from two people whose genetics put them at low risk for AMD.
To simulate aging, Dr. Tsang treated the RPE cells with blue light and a substance called A2E, a natural but toxic byproduct of the biochemical process in the retina that makes vision possible.
He found that the RPE cells at high risk for AMD had greatly reduced anti-oxidant activity when exposed to the aging protocol. That is, the cells were less able to ward off the oxidative stress that has been strongly linked to the development of AMD. In contrast, the low-risk RPE cells retained their anti-oxidative power.
“These variations appear to significantly limit a person’s retinal oxidative defenses,” says Dr. Tsang. “This study suggests that an anti-oxidative treatment, such as the AREDS supplement, is especially important for people at high risk for AMD due to certain ARMS2 and HTRA1 variations.”
He adds that the research also demonstrates why smoking can greatly increase AMD risk, because the habit creates a significant amount of oxidative stress.
Dr. Tsang says that additional studies of the AMD iPSC model will be performed by Jin Yang, Ph.D., his colleague at Columbia University who is setting up a research lab in China. She will be conducting additional studies to understand how the high-risk genetics interact with other genes and affect the health of the retina.
“AMD is a multi-factorial condition. It will take many teams of researchers to fully understand and eradicate the condition,” says Dr. Tsang. “I believe our iPSC model can be helpful to many pharmacologists around the world who are screening for compounds to retard the development of AMD.”
You can learn about other promising AMD research efforts and emerging treatments from the following articles:
Picture, above: Dr. Stephen Tsang. Photo courtesy of Columbia University.