July 19, 2021

From left, Gregory S. Hageman, PhD, SCTM executive director; and Brandi L. Williams, PhD, chromosome 10 research leader and lead author. Image credit: Moran Eye Center

Research conducted at the Sharon Eccles Steele Center for Translational Medicine (SCTM) at the University of Utah’s John A. Moran Eye Center explains why people carrying a block of genetic variants strongly associated with the development of age-related macular degeneration (AMD) may develop the disease and identifies a potential therapeutic pathway for slowing or even reversing disease progression.

AMD is a major cause of irreversible blindness worldwide and the leading cause of blindness for Americans aged 55 and over. Following more than 15 years of research that has employed an extensive repository of donated human ocular tissues, scientists found that HtrA1 protein normally increases with age in the eye at the retinal pigmented epithelium (RPE)-Bruch’s membrane interface, helping to maintain the normal function of this region. The RPE is a cell layer that delivers nutrients to and removes waste from the retina’s light-sensitive photoreceptor cells.

These new data show this is not the case in individuals with AMD-associated risk variants located on chromosome 10. These variants were found to impair expression of the HTRA1 gene by the RPE, resulting in an approximately 50 percent reduction of HtrA1 protein levels at the RPE-Bruch’s membrane interface during aging. The failure to produce adequate levels of HtrA1 protein disrupts this key region of the eye and is associated with AMD-associated pathologies, including the deposition of abnormal deposits and the development of abnormal blood vessels.