Gene Therapy

Gene Therapy, Human Eye
Placeholder Image
Knight Campus researchers
develop gene therapy
for eye disease
By LewiS Taylor
The therapy could eventually provide an alternative treatment for Fuchs’ dystrophy, an eye disease that is the leading cause of corneal transplant surgery
bala ambati
Bala Ambati

Researchers in the Phil and Penny Knight Campus for Accelerating Scientific Impact have developed a new gene therapy that could eventually provide an alternative treatment for Fuchs’ endothelial corneal dystrophy, a genetic eye disease affecting roughly one in 2,000 people globally. Currently, the only treatment is corneal transplant, a major surgery with associated risks and potential complications.

“When you do a transplant you make a huge difference for that person, but it's a big deal for the patient with lots of visits, lots of eye drops, lots of co-pays, and if you had a medical treatment that did not require surgery, that would be great,” said Bala Ambati, a research professor in the Knight Campus and corneal surgeon who led an eight-year study involving the development of the gene therapy. “Not only could it help patients who need a transplant, but it could also help a lot of other people who could have used that (corneal) tissue.”

The results of the study were published in the journal ELife. Investigators focused on a rare, early-onset version of the disease and carried out the research in mice. They used CRISPR-Cas9, a powerful tool for editing genomes, to knock out a mutant form of a protein that is associated with the disease.

Fuchs' dystrophy occurs when cells in the corneal layer called the endothelium gradually die off and stressed cells produce structures known as guttae. These cells normally pump fluid from the cornea to keep it clear, but when they die, fluid builds up, the cornea gets swollen and vision becomes cloudy or hazy. 

“We were able to stop this toxic protein expression and study it in a mouse model,” said Hiro Uehara, a senior research associate in the Ambati Lab and a co-author on the paper. “We confirmed that (in mice who received it), our treatment was able to rescue loss of corneal endothelial cells, reduce guttata-like structures and preserve the corneal endothelial cell pump function.” Corneal cells are non-reproducing, meaning you’re born with all of the cells you will ever have, Ambati said. One of the challenges of the study involved using CRISPR gene editing technology on such cells, a process that is technically difficult. Uehara developed an innovative workaround that increases the utility of the CRISPR technology and could eventually lead to treatments for other diseases involving non-reproducing cells, including some neurologic diseases, immune diseases and certain genetic disorders affecting the joints. The study marks the first time that the technique, called start codon disruption, has been applied to non-reproducing cells.

“It’s potentially expanding the therapeutic target pool for CRISPR-Cas system to tissues that are not capable of cell division,” Ambati said.

The research team — which included Xiaohui Zhang, Sangeetha Ravi Kumar and Bonnie Archer from the Ambati Lab and investigators from the University of Virginia, the University of Utah, the University of Massachusetts and Johns Hopkins University — tested the safety of the treatment by examining surrounding tissues and other genes to make sure they had not been adversely affected by the therapy. Future research will examine the therapy in human donor corneas from eye banks and other animal models with an eye toward eventual clinical testing in humans.

“The mission of the Knight Campus, at the end of the day, is to help people, by bringing scientific advances and by translating projects into products,” Ambati said. “Applied science, translational life science research projects like this one, have clear value to modifying disease and are squarely within the mission of the Knight Campus.”

The research was supported by the National Institutes of Health / National Eye Institute (R01EY017950), a NIH/NEI core grant and an unrestricted grant from Research to Prevent Blindness, Inc. New York, NY. to the Department of Ophthalmology & Visual Sciences, University of Utah.