University of Minnesota researchers uncover possible pathway to prevent AMD

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University of Minnesota Medical School researchers have identified small molecules that can reduce the production of proteins linked to age-related macular degeneration (AMD) — the leading cause of irreversible vision loss among seniors in industrialized nations.

The research was published in JCI Insight.¹

According to a University of Minnesota news release, AMD affects more than 200 million people worldwide.²

"To our knowledge, this is the first demonstration of a small molecule preventing AMD-like pathology in our preclinical model. In the big picture, these results provide hope that AMD may indeed be preventable, or at least modifiable by administration of a single drug," John Hulleman, PhD, an associate professor and Larson Endowed Chair for Macular Degeneration Research at the U of M Medical School and corresponding author, said in the news release.

According to researchers, Malattia Leventinese/Doyne honeycomb retinal dystrophy (ML/DHRD) is an AMD-like retinal dystrophy caused by an autosomal dominant R345W mutation in the secreted glycoprotein, fibulin-3 (F3).

“To identify new small molecules that reduce F3 production in retinal pigmented epithelium (RPE) cells, we knocked-in a luminescent peptide tag (HiBiT) into the endogenous F3 locus that enabled simple, sensitive, and high-throughput detection of the protein,” they wrote. “The GSK3 inhibitor, CHIR99021 (CHIR), significantly reduced F3 burden (expression, secretion, and intracellular levels) in immortalized RPE and non-RPE cells.”

The researchers also explained in the study that low-level, long-term CHIR treatment promoted remodeling of the RPE extracellular matrix, cutting sub-RPE deposit-associated proteins (e.g., amelotin, complement component 3, collagen IV, and fibronectin), while boosting RPE differentiation factors (e.g., tyrosinase, and pigment epithelium-derived factor).

According to the researchers, in vivo, treatment of 8-month-old R345W+/+ knockin mice with CHIR (25 mg/kg i.p., 1 mo) was well tolerated and significantly reduced R345W F3-associated AMD-like basal laminar deposit number and size, thereby preventing the main pathological feature in these mice.¹

“This is an important demonstration of small molecule–based prevention of AMD-like pathology in ML/DHRD mice and may herald a rejuvenation of interest in GSK3 inhibition for the treatment of retinal degenerative diseases, including potentially AMD itself,” the researchers wrote in the study.

By using unbiased drug screening, these inhibitors — specifically targeting a cellular pathway known as GSK3 — were found to prevent AMD features in a preclinical model. The results show that blocking GSK3 at low levels changes certain proteins linked to AMD, effectively preventing the disease in living organisms. 

The next step for the research likely will focus on determining whether blocking GSK3 can reverse existing AMD damage, potentially leading to new treatment options.

Funding for the research was provided by the Fichtenbaum Charitable Trust, Roger and Dorothy Hirl Endowed Research Fund, Edward N. and Della L. Thome Memorial Foundation Award in Age-Related Macular Degeneration Research and National Institutes of Health grants [R01-EY027785, P30-EY030413, S10OD026758-01]. Additional support came from the Promega Advanced Academic Access Program.

References:

1. DiCesare SM, Ortega AJ, Collier GE, et al. GSK3 inhibition reduces ECM production and prevents age-related macular degeneration–like pathology. JCI Insight. 2024;9(15). doi:https://doi.org/10.1172/jci.insight.178050

2. U of M researchers discover potential new pathway to prevent age-related macular degeneration. Medical School. Published August 20, 2024. Accessed August 20, 2024. https://med.umn.edu/news/u-m-researchers-discover-potential-new-pathway-prevent-age-related-macular-degeneration.