A unique retinal model reveals the genetic basis of macular degeneration

A study conducted by the Institute of Genomic Medicine at the University of California, San Diego Medical School uncovered the genetic basis for age-related macular degeneration. These findings were published on the Stem Cell Reports on May 9, 2019.

Age-related macular degeneration (AMD) refers to the aging changes in the structure of the macular area. AMD is mainly due to the decreased ability of retinal pigment epithelial cells to phagocytosis and digestion of the extracellular disk membrane, resulting in the retention of residual membrane bodies that are not completely digested. In the basal cell plasma slurry, it is discharged to the outside of the cell and deposited on the Bruch film to form a drusen. Vitreous hernia is also seen in the elderly with normal vision, but the subsequent pathological changes lead to macular degeneration. AMD is one of the most common causes of vision loss in people over the age of 65, and its prevalence increases with age.

AMD involves the slow breakdown of the cells that make up the macula, which is part of the retina. Retina is located at the back of the eye and is responsible for sending information to the brain. The most common treatment for AMD is to inject a drug that inhibits VEGF. This treatment can prevent the formation of new blood vessels and leakage of abnormal blood vessels.

The exact cause of AMD is unclear, but a family history increases the risk of AMD in a person, suggesting that genetic factors play an important role.

Researchers at the University of California, San Diego School of Medicine first obtained skin samples from participants and then converted skin cells into pluripotent stem cells (iPSCs). Like all stem cells, iPSC can either self-renew, generate more iPSCs, and differentiate into specific cell types. The researchers specifically induced iPSCs to become retinal cells through a mixture of appropriate molecules and growth factors. The resulting eye-in-a-dish model has similar physiological and molecular characteristics to natural retinal cells, including polygons and pigmentation. This eye-in-a-dish model helps them find genetic variations that can result in AMD.

Next, the team collected molecular data on the retinal model, including RNA transcription and epigenetic information. They integrated these new data with supplemental data published by 18 adults with and without AMD. The final conclusion is that the genetic variant most closely related to AMD is rs943080, a special genetic variant that affects the expression of VEGFA genes by altering the activity of a distal region of the genome. Five of the six participants carried a copy of rs943080 and one had two copies of the genetic variant.

Since current AMD therapy works by inhibiting VEGF, it is shown that VEGF is involved in AMD. The team found that although there were only six human samples, the causal variation in the decline in VEGFA expression prior to the onset of AMD may be related to the use of anti-VEGF therapy for AMD.

The product of the VEGFA gene, the VEGFA protein, is known to support the growth of new blood vessels, however this process has presented problems in AMD. Using this new AMD model, the researchers determined that specific genetic variations in the genomic region that regulate VEGFA gene expression reduced VEGFA production and directly led to AMD.

The team published all of their data, allowing researchers around the world the opportunity to further study the molecular characteristics of these iPSC-derived retinal cells. They plan to develop this retinal model for more people and use it to research other genes related to AMD.