Age-related macular degeneration (AMD) is a prominent cause of irreversible vision loss in the United States. Current treatments, while available, offer limited relief and are often accompanied by severe side effects. A groundbreaking study published in Developmental Cell now sheds light on the cellular underpinnings of AMD and opens up possible pathways for innovative treatments.
Dr. Ruchira Singh of the University of Rochester Flaum Eye Institute and Center for Visual Sciences, who spearheaded the research, highlights the limitations of existing AMD therapies. “The treatments currently available for AMD are only partially effective and can have considerable side effects,” she explained. “Our study is focused on uncovering new therapeutic targets that could arrest the progression of AMD and potentially revolutionise treatment approaches.”
To bypass the constraints of prior studies that relied on animal models, Singh’s team utilised human stem cells to create a more accurate model of AMD. This enabled them to examine genes linked to AMD and less common, inherited macular dystrophies. Their research identified a critical protein pivotal in the initial stages of AMD development.
The retinal pigment epithelium (RPE) is integral to the eye’s health and is particularly implicated in AMD. Within the RPE, deposits of proteins and lipids, known as drusen, accumulate, often signalling the onset of AMD. The study pinpointed an overproduction of the protein tissue inhibitor of metalloproteinases 3 (TIMP3) in the RPE of those with AMD. This protein hinders the functioning of matrix metalloproteinase (MMP) enzymes, which are crucial for maintaining ocular health. The impairment of MMP activity, as found in the study, triggers an increase in another enzyme that fosters inflammation and drusen formation.
The researchers employed a novel approach: they used a small-molecule inhibitor to block the activity of the inflammation-promoting enzyme. This intervention successfully reduced drusen accumulation in their AMD model, suggesting that targeting this specific pathway could hold substantial promise for preventing the progression of AMD.
Dr. Singh emphasised the importance of the pathways involved in drusen formation in the progression of AMD. “If we can stop the accumulation of drusen, it might be possible to prevent the disease from advancing to a stage where significant vision loss is inevitable,” she said. “This study not only deepens our understanding of AMD but also presents a beacon of hope for developing therapies that could profoundly benefit the millions suffering from this condition.” This pioneering research marks a significant stride towards deciphering the complexities of AMD and paves the way for potential breakthroughs in treatment strategies that could vastly enhance patient outcomes.
More information: Sonal Dalvi et al, Human iPSC-based disease modeling studies identify a common mechanistic defect and potential therapies for AMD and related macular dystrophies, Developmental Cell. DOI: 10.1007/s00394-023-03123-x
Journal information: Developmental Cell Provided by University of Rochester Medical Center
