Possible Treatment Pathway for Age-Related Macular Degeneration Uncovered

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Researchers at the University of Utah have discovered that low levels of a protein called HTRA1 are likely behind the onset of age-related macular degeneration (AMD) in some individuals and think that raising levels of this protein could be a potential therapeutic strategy.

Levels of HTRA1 function to maintain the area of the eye at the interface between the retinal pigmented epithelium (RPE) and the Bruch’s membrane as people age and normally increase as people get older.

The team, based at the Sharon Eccles Steele Center for Translational Medicine at the University of Utah’s John A. Moran Eye Center, found that genetic variants on chromosome 10 prevent the HTRA1 gene from functioning properly in some people leading to AMD. These genetic variants can reduce HTRA1 protein levels by up to 50%.

It has been known for a while that genetic variants in the 10q26 region of the genome, which contains the genes ARMS2 and HTRA1, have the strongest association with AMD, but it was unclear exactly how these mutations lead to disease. Variants on chromosome 1 are also known to increase AMD risk.

“Our findings are significant because they suggest that HTRA1 normally maintains the integrity of the RPE-Bruch’s membrane interface during the aging process by, in essence, turning over extracellular material and preventing abnormal deposits—including basal laminar deposits—from accumulating between the RPE and Bruch’s membrane,” said Brandi Williams, research director at the John A. Moran Eye Center, and first author on the paper about the work in the Proceedings of the National Academy of Sciences of the United States of America.

“Viewing HTRA1 as protective runs contrary to what one might expect because elevation of HTRA1 protein is thought to be a contributing factor in some diseases such as osteoarthritis,” she added.

The researchers analyzed mRNA levels in eye tissue samples donated by organ donors and found that mRNA encoding HTRA1 was low in RPE tissue, but not in neural retina or choroid tissues. They linked the decrease in levels to a regulatory element that impacts gene expression, which they think becomes less functional in carriers of AMD-related gene variants.

“Consequentially, there is diminished HTRA1 protein within the RPE–Bruch’s membrane interface, the primary site of AMD initiation, with age,” write the authors.

Notably, earlier studies have not linked low HTRA1 levels to AMD symptoms. “Unfortunately, data generated by prior studies have led to the development and testing of therapies—some of which are currently in human clinical trials—designed to reduce overall levels of HTRA1, an approach that may exacerbate AMD progression,” said co-lead author Gregory Hageman, a professor at the John A. Moran Eye Center.

The team are now working on developing a possible therapy for this kind of AMD, based on their findings. “HTRA1 augmentation may be a viable therapeutic option for AMD,” write the researchers.

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