Components of age-related macular degeneration are also important in other conditions, suggesting similarly designed therapies as possible treatments for a range of conditions

With the National Eye Institute reporting that approximately 11 million older adults in the United States have a condition that leads to progressive blindness known as age-related macular degeneration, researchers at the University of Maryland School of Medicine (UMSOM) are beginning to understand what in the disease to develop new therapies to treat it.

Use of human tissue and mice in their new study published June 23 in
Nature communication, they showed that the process of removing the eye’s old, damaged light sensors is disrupted in macular degeneration.

Although more than 50 genes have been linked to the disease, the exact mechanism behind it is unknown. Most people have some form of the disease for which no effective treatments are known.

Zubair M. Ahmed, PhD, Professor of Otorhinolaryngology, Head and Neck Surgery and Ophthalmology at the University of Maryland School of Medicine, had previously been the lead author of a new study found that many families with hearing disorders had genetic mutations in the gene for the CIB2 protein. In a paper published in Nature Genetics in 2012, Dr. Ahmed also that CIB2 is needed for vision in a large human family as well as in zebrafish. In this latest study, his team built on this earlier work to analyze the intricate cellular mechanisms behind retinal degeneration.

The team compared healthy mouse eyes with those of a mouse developed without the CIB2 protein. The researchers observed that the mutant CIB2 mice did not get rid of their old light sensor proteins called photoreceptors, as did healthy mouse eyes.

“Photoreceptors continue to grow in tiny crevices in the eye, but over time, light damages the photoreceptors. To combat this, the supporting cells in the eye slowly nibble on the old, damaged photoreceptors to keep the columns the correct length, ”says first author Saumil Sethna, PhD, Instructor of Otorhinolaryngology-Head & Neck Surgery at the University of Maryland School of Medicine. “If the photoreceptors are not removed or the process is supported by the slow digestion by the supporting cells, as in the CIB2 mutant mice, the undigested material builds up over time, which can contribute to blindness.”

Next, the researchers identified several components in this photoreceptor recycling process, including a group of proteins collectively known as mTORC1 that are implicated in many human diseases, including cancer, obesity, and epilepsy.

Since mTORC1 plays a key decision-making role in many cellular functions, including cleaning up cell debris, the researchers examined the activity of mTORC1 in the mutant CIB2 mice and found that mTORC1 was overactive. They confirmed that mTORC1 was also overactive in human eye tissue samples from people with some form of age-related macular degeneration. By linking the results of the mouse studies to human disease, the researchers say their results suggest that drugs for mTORC1 may be effective treatments for the most common type of age-related macular degeneration. mTOR, the core component, is available in two versions, each with different functions, known as complex 1 (as in mTORC1) or complex 2 (mTORC2).

“Researchers have tested many small molecules that target mTORC1 to treat various diseases, but the problem is that mTOR is needed for so many other cell functions that there are significant side effects when doing crafting,” says Dr. Ahmed. “In our study, we found a backdoor to mTORC1 (and not mTORC2) regulation that can bypass many of the nasty side effects normally associated with mTORC1 suppression. We believe that we can use our new knowledge about this mechanism to develop treatments for age-related macular degeneration and other diseases. ”

The authors have filed a patent application to develop new therapies that use the role of CIB2 in the control of mTOR (PCT / US2019 / 044745).

“Understanding the cell mechanisms behind age-related macular degeneration is the first step in developing new treatments,” said E. Albert Reece, MD, PhD, MBA, executive vice president for medical affairs, UM Baltimore, and the John and Z. and Akiko K Bowers Distinguished Professor and Dean, University of Maryland School of Medicine. “Using the evolving understanding of the mechanistic role of mTORC1, this study has provided great insight into new ways researchers can find ways to preserve, treat, and / or improve macular degeneration, thereby improving quality of life and independence Live in many older adults. “

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Other authors on the study include Arnaud Giese, Steven Bernstein, and Saima Riazuddin from the University of Maryland School of Medicine; Patrick Scott of the University of Louisville; Xiaoying Jian and Paul Randazzo from the National Cancer Institute; Todd Duncan and T. Michael Redmond of the National Eye Institute; and Sheikh Riazuddin of Allama Iqbal Medical College.

This work was supported by grants from the National Institute on Deafness and Other Communication Disorders (R01DC012564, R01DC016295, and R56DC011803), the Loris Rich Postdoctoral Fellowship from the International Retinal Research Foundation, and the Research to Prevent Blindness Award.

About the University of Maryland School of Medicine

The University of Maryland School of Medicine is in the third century and was founded in 1807 as the first public medical school in the United States. It is now one of the fastest growing, leading biomedical research companies in the world – with 45 academic departments, centers, institutes and programs; and a faculty of more than 3,000 physicians, scientists, and related health professionals, including members of the National Academy of Medicine and the National Academy of Sciences, and a distinguished two-time winner of the Albert E. Lasker Award in Medical Research. With an operating budget of more than $ 1.2 billion, the School of Medicine works closely with the University of Maryland’s Medical Center and Medical System to provide research-intensive, academic, and clinically-sound care to nearly 2 million patients each year. The School of Medicine has more than $ 563 million in extramural funding, with most of its academic departments ranked high among all medical schools in the country in research funding. As one of the seven professional schools that make up the University of Maryland, Baltimore campus, the School of Medicine has a total population of nearly 9,000 faculty and staff, including 2,500 students, residents, and fellows. The combined School of Medicine and Medical System (University of Maryland Medicine) has an annual budget of nearly $ 6 billion and has an economic impact of more than $ 15 billion on the state and local community. Ranked 8th among public medical schools in terms of research productivity, the School of Medicine is an innovator in translational medicine with 600 active patents and 24 start-ups. The School of Medicine works locally, nationally and globally with research and treatment facilities in 36 countries around the world. Visit medschool.umaryland.edu

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