HtrA1 Augmentation Promising for Chromosome 10-Driven Age-Related Macular Degeneration

NEW YORK (Reuters Health) – Augmenting the HtrA1 protein is a potential therapy for patients at high risk for chromosome 10-driven age-related macular degeneration (AMD), researchers say.

The HTRA1 (high temperature requirement A serine peptidase 1) gene provides instructions for making a protein that is found in many of the body’s organs and tissues. In the eye, it normally increases with age at the retinal pigmented epithelium (RPE)-Bruch’s membrane interface, helping to maintain the normal function of this region.

“Genome-wide association studies published in 2006 identified a significant association between an individual’s risk for developing AMD and a region of chromosome 10 encompassing the ARMS2 and HTRA1 genes,” Dr. Gregory Hageman of the John A. Moran Eye Center at the University of Utah in Salt Lake City told Reuters Health by email. “Since that time, scientists and clinicians have strived to characterize the biological underpinnings of this locus and their relationship to disease causality.”

“The results of (our) studies unequivocally demonstrated that HTRA1 mRNA and protein levels were significantly reduced within the RPE and the RPE-Bruch’s membrane complex derived from donors with Chr10 risk,” he said.

“In stark contrast,” he added, “accumulation of HtrA1 protein within this complex in Chr10 non-risk donors occurred in an age-dependent manner.”

“The findings of this study were unexpected, as previous studies suggested that HTRA1 levels were unchanged or elevated with risk,” he noted. “As a result, various preclinical studies and clinical trials have been initiated to treat individuals with AMD using small molecule inhibitors or antibodies directed against HtrA1, with the goal of reducing overall levels and/or activities of HtrA1 protein.”

However, based on the results of the current study, he said, “and provided these inhibitors or antibodies reach the primary site of AMD pathology, these inhibitory therapeutic approaches may actually exacerbate disease progression in individuals with chromosome 10-directed AMD.”

As reported in Proceedings of the National Academy of Sciences of the United States of America, Dr. Hageman and colleagues show in a series of experiments using hundreds of donated human ocular tissue samples that HTRA1 mRNA is reduced in the RPE, but not in neural retina or choroid tissues derived from donors with homozygous risk at the 10q26 locus. However, analyses showed “a strong accumulation of HtrA1 protein” in samples from donors who were not at risk.

As Dr. Hageman indicated, the tissue-specific decrease at the 10q26 locus is mediated by variants that disrupt a cis-regulatory element within that locus, resulting in an approximately 50% reduction of HtrA1 protein levels at the RPE-Bruch’s membrane interface with age. Failure to produce adequate levels of HtrA1 protein is associated with AMD-associated pathologies, including the deposition of abnormal deposits and the development of abnormal blood vessels.

Dr. Hageman said, “These data imply that treatments developed to correct these deficits in HtrA1 levels may be beneficial in preventing disease initiation and progression, thus slowing loss of vision. We are currently advancing various approaches to augment HTRA1 expression within the RPE and adjacent tissues, including gene therapy and CRISPR-based therapies.”

Vitreoretinal surgeon Dr. Nimesh Patel of Mass Eye and Ear in Boston commented in an email to Reuters Health, “The study appears to have sound methodology to support the conclusion. It does contradict findings in some previous investigations; however, those did not use choroidal and RPE tissue, which is the actual site of dysfunction in AMD.”

“This is still an early laboratory study,” he said. “It suggests that HRTA1 levels are impaired by AMD risk-associated variants, but the significance of this is unknown. If it is proven that the HRTA protein is a key factor in maintaining the retinal health, it may be able to be supplied by direct intravitreal injection into the eye to slow the progression of AMD.”

“Additionally,” he noted, “if the genes responsible for the protein are isolated, it is possible that they could be replaced with gene therapy, which is an advancing area of therapeutics in AMD.”

“It is exciting to see possible new therapeutic targets in AMD, given the high prevalence of the disease,” he said. “However, further studies are needed to provide validation and to assess viability as a clinically relevant factor.”

SOURCE: Proceedings of the National Academy of Sciences of the United States of America, online July 27, 2021.

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