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Scientists Clarify Genetic Risk for Developing Age-Related Macular Degeneration, Identify Protective ‘Ace in the Hole’

Newly published research hones in on genetic protection to advance new treatment approaches.

Researchers studying age-related macular degeneration (AMD) have clarified what constitutes genetic risk or protection for the blinding disease, showing that certain forms of protection amount to an "ace in the hole" that can overcome an equal amount of risk.

A cluster of six genes on chromosome 1 and a pair of genes on chromosome10 are the most highly associated with the development of AMD, accounting for more than 90 percent of risk attributable to genetic factors. Scientists at the Sharon Eccles Center for Translational Medicine (SCTM) at the University of Utah’s John A. Moran Eye Center have now shown that protective combinations of genetic variants, or haplotypes, on chromosome 1 outweigh risk for people with equal numbers of risk and protective haplotypes.

Perhaps the most significant news from the SCTM, led by Gregory S. Hageman, PhD, is that the haplotypes within the chromosome 1 locus protect against both chromosome 1- and 10-directed AMD.

"This finding opens up the possibility that therapeutics designed to target the form of AMD driven by risk on chromosome 1 may also be effective in treating the vast majority of AMD, regardless of genetic cause," explained co-first author Moussa Zouache, PhD.

The SCTM has developed a targeted therapy for individuals at risk for chromosome 1-directed AMD based on these findings and are advancing it into human clinical trials to determine its safety and efficacy.

"We couldn’t be more excited," said Hageman. "These data indicate that introducing protective genetic material into the eye may slow or even stop disease progression for people who have a high risk at chromosome 1 and/or chromosome 10."

The researchers used information collected from 4,784 study patients to reach their conclusions. Access to the SCTM’s extensive repository of nearly 10,000 donated human eyes with and without AMD was also essential to the effort.

The SCTM’s research supports a precision medicine approach to AMD, a leading cause of blindness for people age 55 and older.

"There are risk, protective, and neutral AMD haplotypes, and the combination of these haplotypes establishes your genetic predisposition to AMD," said co-first author Chris Pappas. "This information can be used to assess an individual’s genetic risk and to tailor treatments to that risk."

The research findings are reported in "Protective chromosome 1q32 haplotypes mitigate risk for age-related macular degeneration associated with the CFH-CFHR5 and ARMS2/HTRA1 loci," published in Human Genomics. Authors are: Chris M. Pappas, Moussa A. Zouache, Stacie Matthews, Caitlin D. Faust, Jill L. Hageman, Brandi L. Williams, Burt T. Richards and Gregory S. Hageman.

The work was supported in part by the National Eye Institute of the National Institutes of Health under award number R24EY017404 and Voyant Biotherapeutics LLC. Additional support from philanthropic donations to the Steele Center for Translational Medicine and an Unrestricted Grant from Research to Prevent Blindness, New York, NY, to the Department of Ophthalmology and Visual Sciences, University of Utah.

A chart accompanying newly published research that hones in on genetic protection to advance new treatment approaches.
A chart accompanying research that protective combinations of AMD genetic variants, or haplotypes, on chromosome 1 outweigh risk for people with equal numbers of risk and protective haplotypes.

About the John A. Moran Eye Center

The John A. Moran Eye Center at the University of Utah serves as the largest ophthalmology clinical care and research facility in the Mountain West, with more than 60 faculty members and 10 satellite clinics. Physicians provide comprehensive care in all ophthalmic subspecialties, making the Moran Eye Center a major referral center for complex cases with over 157,000 patient visits and about 9,000 surgeries annually.

Moran supports 16 research laboratories and centers. Its Sharon Eccles Steele Center for Translational Medicine uses public-private partnerships to turn lab discoveries into therapies quickly. Moran CEO and Chair of Ophthalmology and Visual Sciences Randall J Olson, MD, leads more than 500 employees working to achieve the Moran Eye Center’s vision that no person with a blinding condition, eye disease, or visual impairment should be without hope, understanding, and treatment.