The work targets a leading delivery method for the therapies, adeno-associated virus (AAV), and recently was published in the journal by UofL’s Maureen A. McCall and her colleagues from Harvard University and its Wyss Institute.

AAV is used in treating a number of conditions, including the retinal diseases McCall studies at UofL. However, it also has been known to cause serious side effects, such as elevated immune response and inflammation.

“It’s a real problem since there’s no real control,” said McCall, the Kentucky Lions Eye Research Endowed Chair and a professor in the Departments of Ophthalmology and Visual Sciences and Anatomical Sciences and Neurobiology. “Even with the best-laid plans, you see some inflammatory retinal response, and the amount can vary widely, including dangerous levels.”

The new research focuses on the role of the viral capsid, a component in AAV that’s believed to cause this response. Parts of the viral capsid interact with a protein known as Toll-like receptor 9 (TLR9), which senses foreign DNA in the body. TLR9 triggers the immune response, which causes inflammation and can reduce or eliminate the therapy’s effects.

“So, the hypothesis was that if you could change that capsid code and mask it from the Toll-like receptor, that you could build a better delivery tool,” McCall said.

The idea is to “cloak” the deleterious part of the capsid with a series of synthetic DNA “inflammation-inhibiting oligonucleotide” sequences meant to stop TLR9’s reaction. In mouse models, the researchers saw a 95% reduction in inflammation.

In many cases, gene therapies for optical diseases are delivered through the retina since the blood-retina barrier helps to mitigate some of the immune response. Ying Kai Chan, a former postdoctoral fellow in George Church’s group at the Wyss Institute, reached out to McCall in 2018 to partner on this work because of her research expertise and the experience of her UofL colleagues with these injections, especially Wei Wang, assistant professor of ophthalmology.

McCall’s work at UofL specifically focuses on the use of gene therapies to treat retinal diseases, including retinitis pigmentosa and other conditions that eventually can cause blindness. For some of these conditions, there is no known cure and many therapies are still in development and clinical trials. McCall said eliminating side effects associated with AAV delivery gets researchers one step closer to successful treatment.

“Solving this key problem with delivery is huge,” she said. “These therapies show promise in significantly increasing people’s quality of life. My hope is that one day we can use these therapies to slow – or even stop – the progression of these diseases and restore sight.”

Established in 2002, the RPB Walt and Lilly Disney Award for Amblyopia Research is intended to stimulate, strengthen and promote research to improve the diagnosis and treatment of amblyopia. The grant is offered to exceptional ophthalmic scientists – MDs or PhDs – with research pursuits of potential significance and promise. McGee is one of two scientists to receive the award in 2016.

“Dr. McGee’s funding from RPB addresses a major cause of blindness in children – namely, amblyopia. The potential to reverse ‘lazy eye’ through medical therapy would be a major advance in curing childhood visual disabilities and improve the quality of life for those affected. His research is exciting and has major potential translational clinical impact,” said Henry Kaplan, MD, chair of the UofL Department of Ophthalmology and Visual Sciences.

Amblyopia occurs in 2 to 3 percent of children and presents with a number of impairments in spatial vision including stereopsis, or depth perception. Permanent visual deficits may result if amblyopia is not treated during a critical period for development of the visual system that ends in early adolescence. The funded research builds on McGee’s previous work investigating how the timing and duration of critical periods in the visual system are determined. McGee will test methods for reversing the loss of depth perception resulting from amblyopia by “re-opening” the critical period in adulthood to enhance the flexibility, or plasticity, of brain circuitry.

“Previously, we discovered that a gene encoding a neuronal receptor is essential for closing the critical period for visual plasticity,” McGee said. “This award from RPB will enable my lab to explore whether neutralizing this receptor will improve depth perception in the murine model of amblyopia.”

McGee moved from the University of Southern California to join the UofL Department of Ophthalmology and Visual Sciences and Department of Anatomical Sciences and Neurobiology in September 2016. The goals of his research program are to identify treatments for low vision and aberrant eye dominance by understanding critical periods for neural plasticity and how experience drives changes in brain function.

The Disney Award for Amblyopia Research is a two-year award to help the awardee pursue promising scientific leads and take opportunities for which other funds are not readily available. RPB is the world’s leading voluntary organization supporting eye research. Since it was founded in 1960, RPB has provided hundreds of millions of dollars to support research into blinding eye diseases by medical institutions throughout the United States.