Andrei Tkatchenko, MD, PhD
The Genetics of Myopia
With its global prevalence expected to reach 50% by 2050, myopia has emerged as one of the leading causes of vision loss in several parts of the world. The excessive eye growth that produces nearsightedness also leads to serious vision-threatening complications such as retinal tears and detachment, myopic macular degeneration, and glaucoma (see feature, page 3).
Andrei V. Tkatchenko, MD, PhD, Associate Professor of Ophthalmic Sciences (in Ophthalmology and Pathology and Cell Biology), made international headlines in 2015 when he identified variations in the gene APLP2 as an important factor in the development of myopia in children. His latest research, published in PLOS Biology in October 2018, identifies two distinct molecular signaling pathways involved with the mechanisms controlling eye growth and optical development. Understanding these pathways is an essential step toward developing candidate drugs to effectively treat myopia.
“While there are some optics-based treatments and drugs that can be used now to slow progression of myopia, their effectiveness is limited,” Dr. Tkatchenko says. “The main obstacle that prevents us from developing more effective therapies is our incomplete knowledge of the molecular mechanisms that control visually guided eye growth and development. We hope that our research will help to overcome that obstacle.”
What Causes Myopia?
The majority of babies are born hyperopic, or farsighted, which means that a typical newborn can see a teddy bear located on the other side of the room much better than if it’s near her face.
“In infants, the anterior segment of the eye—the region that includes the cornea, anterior chamber and crystalline lens—is almost fully developed, but the posterior segment is very small in most cases,” explains Dr. Tkatchenko. “As a result, images are focused behind the retina, which leads to farsightedness. During the first years of life, eyes gradually develop focus through a process known as emmetropization, as the length of the eye increases until the focal point coincides with the retina. When images are focused precisely on the retina, an individual has perfect vision and can see well both near and at a distance.” But in an increasing number of children, the length of the eye continues to grow beyond that point of perfect vision, causing myopia.
Scientists have long believed that myopia is caused by an interacting combination of environmental and genetic factors, but until recently, hard proof of this theory was lacking. Then, in research published in PLOS Genetics in 2015, Dr. Tkatchenko and colleagues showed that children with a specific variation of APLP2 have an increased susceptibility to myopia—but only if they spend large amounts of time per day reading or doing other close work. “We found that children with this variation were five times more likely to develop myopia if they also spent at least an hour a day reading,” he says. The study was the first known evidence of gene-environment interaction in myopia.
Two Different Pathways
Dr. Tkatchenko’s latest research builds on those findings and challenges a commonly held assumption about myopia and hyperopia: that these two ocular conditions are caused by opposing changes in the same genes and pathways. Instead, Dr. Tkatchenko’s group found that distinctly different molecular pathways are activated in myopia and hyperopia.
In a primate model, Dr. Tkatchenko and colleagues used specially designed contact lenses to induce the development of either myopia or hyperopia. They observed that the animals’ eyes were stimulated to either increase or decrease their axial length (the distance between the front and back of the eye) in response to the artificially created defocus. Next, they conducted a wholegenome gene expression analysis on each of the retinas that had been treated with optical defocus. They identified large-scale changes in gene expression controlling metabolism and cell signaling in the retina—but those changes involved almost completely different sets of genes and signaling pathways for hyperopia and myopia.
“Our findings show that the retina can distinguish between myopic and hyperopic defocus,” Dr. Tkatchenko says. “Now that we have identified the pathways underlying the eye’s response to optical defocus, we have a better understanding of the mechanisms that control refractive eye development. Our next step will be to identify druggable targets within these pathways, and candidate drugs that can modulate those targets and counteract the development of myopia.”