Editing Genes to Treat Corneal Dystrophies

Gene editing therapy—making changes to the DNA of cells to correct mutations—is a promising avenue to treat inherited ocular defects and blinding disorders.

Much research is devoted to applying gene editing to conditions of the retina. Yet, as ophthalmic geneticist Lev Prasov, M.D., Ph.D., and cornea specialist Shahzad Mian, M.D., note, far less attention has been paid to how gene editing might be used to treat corneal dystrophies, which impact about one in 2,000 Americans.

“Corneal dystrophies are good therapeutic candidates for gene editing,” says Dr. Prasov. “Specific genetic mutations common to several dystrophies have already been identified. Moreover, those genes have been shown to be amenable to manipulation with editing tools like CRISPR-Cas9 base editing.”

Dr. Mian sees two promising paths for using gene editing to treat inherited corneal dystrophies. The first is early intervention. “This could prove a sightsaving approach for a patient identified as carrying a mutation whose disease has not yet progressed to a completely opaque cornea.”

The second is treating dystrophies that recur in corneal grafts. “Recurrence is all too common in corneal transplants,” Dr. Mian says. “If we could ‘edit out’ the genetic culprit, it would save many patients from needing multiple transplants.”

The Research Scouts Program, a new funding initiative at the U-M Medical School Office of Research, was the perfect opportunity to develop this project. The program empowers a team of U-M researchers (‘scouts’) to identify bold early-stage ideas and spark the needed connections across the medical campus to make them happen.

The idea caught the attention of ‘scout’ Ivo Dinov, Ph.D., who introduced Drs. Prasov and Mian to Yan Zhang, Ph.D., a researcher in the Department of Biological Chemistry. Dr. Zhang is an expert in developing and applying CRISPR-based technologies to tackle diverse biological challenges.

With funding from a Research Scouts grant, their collaboration will focus on two types of genetically linked corneal dystrophies both linked to disruption of the same protein (TGFBI): lattice and granular.

Mining data from electronic medical records, Drs. Prasov and Mian will identify Kellogg patients with those corneal dystrophies for genetic testing. Separately, they will use donor corneal tissue to test different methods of delivering a treatment into the cornea to modify the gene. Dr. Zhang will apply the latest CRISPR technology to design various gene editing reagents, evaluating them first in corneal cell lines, then in corneal tissue samples to identify the reagent that produces the optimal editing change.

They hope the project will generate enough data to apply for larger NIH and/or foundation funding. “We could not have pursued this idea without Dr. Zhang, and we would likely never have connected with her had it not been for the Scout program,” says Dr. Mian. “It’s a testament to what’s possible in an institution that fosters collaboration and prioritizes bold science.”

Header image caption: Yan Zhang, Ph.D., Shahzad Mian, M.D., Lev Prasov, M.D., Ph.D.