Recently, research led by Dr. Francesca Marassi, a professor at Sanford Burnham Prebith, is helping to reveal the molecular secrets of macular degeneration, which causes almost 90% of age-related vision loss. The study, recently published in Biophysics, describes the flexible structure of a key blood protein that is associated with macular degeneration and other age-related diseases such as Alzheimer’s disease and atherosclerosis.
Marassi said: “Because blood flows in different ways throughout the body, proteins in the blood are under changing pressures.” “For example, blood flows more slowly in the small blood vessels of the eye than in the large arteries around the heart. Blood proteins need to be able to respond to these changes, and this study provides us with basic facts about how they adapt to the environment, which is essential for future therapeutics to target these proteins.”
There are hundreds of proteins in our blood, but researchers are mainly concerned about vitamin c, which is one of the most abundant proteins. In addition to circulating at high concentrations in blood, vitronectin is present in scaffolds between cells and is an important component of cholesterol.
Vitronectin plays a key role in many age-related diseases, but for Marassi ‘s team, the most promising target is macular degeneration, a disease that affects as many as 11 million people in the United States. This number is expected to double by 2050.
“This protein is an important target for macular degeneration because it accumulates in the back of the eye, leading to decreased vision. Similar deposits appear in the brains of Alzheimer ‘s patients and in the arteries of atherosclerotic patients,” Marassie says. “We want to understand why this happens and use this knowledge to develop new treatments.”
To address this issue, researchers are interested in understanding how proteins change their structure at different temperatures and pressures to approximate what happens in the human body.
“Determining the structure of a protein is the most important part of determining its function,” Marassi added. Through detailed biochemical analysis, the researchers found that the protein can subtly change its shape under stress. These changes make it easier to bind to calcium ions in the blood, which the researchers believe leads to the accumulation of calcified plaque deposits that are characteristic of macular degeneration and other age-related diseases.
Marassi said: “This is a very subtle rearrangement of molecular structures, but it has a great impact on the function of proteins.” “The more we understand the structure and mechanism of this protein, the more likely we are to successfully target it for treatment.”
These structural insights will simplify the development of macular degeneration treatments, as it will allow researchers and their partners in the biotechnology industry to customize the design of antibodies that selectively block calcium binding of proteins without disrupting their other important functions in vivo.
“It takes some time to translate it into clinical treatment, but we hope to have an effective antibody as a potential treatment within a few years,” Marassi said. “Because this protein is so abundant in blood, this new knowledge may have other exciting applications that we don’t even know yet.”
