HtrA1 Augmentation as Potential Therapy for AMD

Article: HtrA1 Augmentation is Potential Therapy for Age-Related Macular Degeneration
Source: University of Utah Health, via NEI
Published: July 19, 2021

Analyses of HtrA1 protein in human donor ocular tissues (A–D),
comparing homozygous nonrisk or risk genotype groups. Note that
there is only a difference between nonrisk and risk in the RPE-choroid.

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in individuals over the age of 55. Fifteen years of research identified HtrA1 protein, a serine protease enzyme encoded by the HTRA1 gene, as normally increasing with age in the retinal pigmented epithelium (RPE)-Bruch’s membrane interface, and helps to maintain normal RPE function to deliver nutrients and remove waste from the eye's photoreceptors. The present research shows that individuals with AMD-associated risk variants located on chromosome 10 have impaired expression of the HTRA1 gene, resulting in approximately 50% reduction in HtrA1 protein levels at the RPE-Bruch’s membrane interface during aging. The resulting dysfunction leads to abnormal deposits and blood vessels characteristic of AMD. The team found that reduced HTRA1 mRNA was only a risk factor in the RPE, and not in the neural retina or the choroid. According to the lead author of the study, seeing HtaA1 as protective in maintaining the RPE-Bruch's membrane interface is unexpected, given that HtrA1 protein is thought to contribute to diseases such as osteoarthritis. The discovery, however, was made possible by a unique repository of more than 8,000 pairs of donated human eyes to sample chromosome 10-directed AMD, narrowing down a smaller causal region of chromosome 10 that is likely responsible for reduced expression of HTRA1, and specifically studying HTRA1 expression in the RPE-Bruch’s membrane interface (the primary site of AMD pathogenesis) compared to the neural retina or white blood cells as was done in prior studies. The senior researcher adds, “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.” While such contradictions might seem alarming, novel discoveries that expand and refresh the literature, and discussion about findings of different research studies, are commonplace in the scientific enterprise, including biomedical research. The research team is currently working on therapies for individuals with AMD due to mutations in chromosome 1 or chromosome 10, which, according to the researchers, together account for more than 50% of the genetic risk for developing AMD.

My rating of this study: ⭐⭐⭐

Williams BL, Seager NA, Gardiner JD, et al. "Chromosome 10q26–driven age-related macular degeneration is associated with reduced levels of HTRA1 in human retinal pigment epithelium." PNAS.  118(30):e2103617118. 27 July 2021. https://doi.org/10.1073/pnas.2103617118