New research on AMD, a leading cause of vision loss, identifies the protein TIMP3 as a key player in disease progression. By using stem cells to model AMD, scientists reduced harmful drusen formation, offering a potential new treatment strategy to halt the disease.
Age-related macular degeneration (AMD) is a major cause of permanent vision loss in the United States. While current treatments exist, the root causes of the disease and fully effective therapies remain unclear. However, recent research published in Developmental Cell sheds light on the cellular mechanisms driving AMD and suggests new potential treatment strategies.
“Current treatments for AMD have limited efficacy and often come with significant side effects,” said Ruchira Singh, PhD, with the University of Rochester Flaum Eye Institute and Center for Visual Sciences, and lead author of the study. “Our research aims to identify novel therapeutic targets that could potentially halt the progression of this disease.”
The study utilized human stem cells to model AMD, overcoming the limitations of previous research using animal models. By examining genes associated with both AMD and rarer inherited forms of blindness called macular dystrophies, the researchers identified a key protein involved in the early stages of the disease.
The retinal pigment epithelium (RPE), a layer of cells at the back of the eye, plays a crucial role in AMD. Over time, deposits of lipids and proteins, known as drusen, accumulate in the RPE. These deposits are often an early indicator of AMD.
Discovery of Key Protein Involved in AMD
The researchers discovered that a protein called tissue inhibitor of metalloproteinases 3 (TIMP3) is overproduced in AMD. TIMP3 inhibits the activity of enzymes called matrix metalloproteinases (MMPs), which are essential for eye health. Impaired MMP activity leads to an increase in another enzyme which promotes inflammation and the formation of drusen.
By using a small molecule inhibitor to block the activity of the enzyme associated with inflammation, the researchers were able to reduce drusen formation in their model, suggesting that targeting this pathway could be a promising strategy for preventing AMD.
“Cellular pathways involved in drusen formation are key drivers of AMD progression,” said Dr. Singh. “If we can halt the accumulation of drusen, we may be able to prevent the disease from progressing to a stage where vision loss occurs. This research offers hope for developing new treatments that could significantly improve the lives of millions of people affected by AMD.”
Reference: “Human iPSC-based disease modeling studies identify a common mechanistic defect and potential therapies for AMD and related macular dystrophies” by Sonal Dalvi, Michael Roll, Amit Chatterjee, Lal Krishan Kumar, Akshita Bhogavalli, Nathaniel Foley, Cesar Arduino, Whitney Spencer, Cheyenne Reuben-Thomas, Davide Ortolan, Alice Pébay, Kapil Bharti, Bela Anand-Apte and Ruchira Singh, 2 October 2024, Developmental Cell.
DOI: 10.1016/j.devcel.2024.09.006
Additional co-authors include Sonal Dalvi, Michael Roll, Amit Chatterjee, Lal Krishan Kumar, Akshita Bhogavalli, Nathaniel Foley, Cesar Arduino, Whitney Spencer, and with the University of Rochester, Cheyenne Reuben-Thomas, Davide Ortolan and Kapil Bharti with the National Eye Institute, Alice Pebay with the University of Melbourne, and Bela Anand-Apte with the Cleveland Clinic. The research was supported by the National Eye Institute, ForeBatten Foundation, and Research to Prevent Blindness.