When there is a gap in the eye

By: Ehsan Misaghi, University of Alberta

There is no doubt that our eyes are essential to us and our day-to-day activities. A defect in our eyes can have devastating effects on our lives, especially if the defect is large enough, as in the case of blindness. Worldwide, about 10-15% of childhood blindness comes from a disease called coloboma.

Development of the eye requires the normal functioning of multiple complex processes in the first few months and years of life and any defects in those processes can cause problems in the eye. Coloboma is defined as the presence of a hole in at least one of the eye structures, such as the retina, iris, cornea, or eyelid. Symptoms of coloboma can vary depending on where and how large the defect is. They can range from no symptoms to light sensitivity to reduced vision and even blindness. As part of my PhD, I’m researching the genetic causes of coloboma, with the hopes of developing methods to fix broken genes that cause this condition.

Coloboma is a developmental disorder, i.e., it happens before birth. Parents of kids with coloboma usually notice a pinhole-like defect in the eye and rapidly failing eyesight. Sometimes the defect is not even visible, and they only notice light sensitivity or vision loss. Often, they have to go through multiple specialists to get a diagnosis. All we can do right now to “treat” this condition is to use glasses to improve the vision just a little bit. Depending on the location of coloboma in the eye, that might not even work. There are many stories like this of people who have coloboma and basically live with very limited or no eyesight. Wouldn’t it be great if we could figure out what causes this and maybe prevent or treat it?

During the development of the eye, two openings form, one above and one below the eye. These openings are there to let the blood vessels into the eye and the nerves of the eye out into the brain. Once that’s done, they both close. If either of these openings don’t close like they are supposed to, coloboma happens. Coloboma in the opening below the eye is the most common type. Our lab at the University of Alberta (the Waskiewicz lab), however, has discovered that this can happen in the opening above the eye as well, which we have called superior coloboma.

Our lab has shown that cell orientation (known as polarity) might have something to do with coloboma and eye development. Polarity defines how cells orient themselves with regards to each other, which determines where cells go, stay and form tissues and organs in the body. There is a lot of research showing the importance of polarity in the development of the hair on the skin and inside the ears and in the development of the kidneys. However, the role of polarity in the development of the eye hasn’t been explored as much, even though the building blocks of the tissues in all these organs are similar.

I’m investigating the role of cell polarity in the development of the eye and in coloboma, especially superior coloboma. In our lab, we have looked at the genes of 6 patients with superior coloboma and we have seen that most of these patients have defective genes that are involved in cell polarity, which suggests that their cells in that part of the eye don’t know how to organize themselves and form the needed tissue. We have tried creating defects in some of these genes in zebrafish and have shown that the closure of the opening above the eye can be delayed, which means these genes have a role in the closure of the opening.

Even though we have found that specific genes are defective in patients with coloboma, we don’t know if they are the actual cause of this disorder, yet. My role, therefore, is to find which gene or combination of genes are primarily responsible for the closure. I can do this by creating defects in extra genes using newer technology, such as CRISPR-Cas9, which can act like a pair of scissors that cuts the DNA and thus induces a defect in the gene of interest. I will also investigate multiple other genes outside of the genes involved in cell polarity to determine if any other processes are involved in the closure of the openings above and below the eye. However, at this point, we are not sure what those genes are going to be.

I’m hoping that as a result of my work, we can determine the causative genes of coloboma. This can lead to the development of newborn screening panels, such as the ones we currently do for other genetic disorders such as Down syndrome. I am also hoping that my work can pave the way for developing therapies to treat or cure this disorder.

Edited by B.G. Borowiec and A.E. McDonald. Header photo from Wikimedia Commons.