Blindness and liver: a link at the gene level
In 2005, two genome–wide associative studies involving patients suffering from macular degeneration, a disease that is the most common cause of blindness in people over 65 years of age, led to an unexpected discovery. It turned out that the risk of macular degeneration is significantly increased by defects in the gene encoding Complement Factor H (CFH) synthesized in the liver. This protein is the main inhibitor of the complement system involved in the formation of immune responses of the body.
The yellow plaques on the retina image are druses, a characteristic sign of macular degeneration. These plaques consist of proteins that are part of the complement system, the connection of which with the disease was also revealed during genetic studies.
Since then, researchers have identified a number of variants of several related genes with a similar effect. All currently known genetic variants determine a 50-60% chance of getting age-related macular degeneration.
Before the discoveries of 2005, few specialists in macular degeneration suspected that the complement system involved in the elimination of pathogens from the body plays a major role in the pathogenesis of this disease. The identification of the relationship between macular degeneration and the complement factor H gene, as well as other related genes, allowed researchers to look at the disease from the other side. Experiments have shown that the absence of complement factor H causes eye and kidney diseases in mice. (The structure of the retina in mice differs from that of humans, so it is impossible to create an adequate mouse model of macular degeneration.)
In the same 2005, Dr. Gregory Hageman identified a variant of the CFH gene found in about 20% of people that protects against the development of macular degeneration (the presence of two copies of this genetic variant practically excludes the possibility of developing the disease). He subsequently founded Optherion, a company based in New Haven, Connecticut, and began working on translating his findings into new treatments. Currently, Optherion produces a huge number of synthetic versions of the protein product of the protective gene and is actively engaged in preclinical research of its safety and effectiveness. However, the president of the company refused to predict the start date of clinical trials.
Hageman left Optherion some time ago. He now works at the University of Utah and is developing alternative methods for using the protective variant of complement factor H. This protein is synthesized mainly by liver cells, so Hageman's group is studying the features of the course of macular degeneration in patients who have undergone liver transplantation. The researchers described a number of cases when, after liver transplantation of a donor with a high risk of the disease, recipients rapidly developed macular degeneration. At the same time, they found a couple of cases when liver transplantation of a donor with a protective version of complement factor H stopped the progression of an existing disease. However, Hageman emphasizes that the data available to date is insufficient to obtain statistically reliable results.
The mechanisms by which different variants of complement factor H contribute to the development of macular degeneration or prevent it are still unclear.
Experts suggest that certain mutations disrupt the ability of the studied gene to adequately control the functioning of the complement system, which begins to attack the body's own cells. Chronic complement activation and chronic lack of control over its work are a possible explanation for the age-related nature of macular degeneration.
The identification of the link between eye disease and the protein synthesized in the liver clearly demonstrates the benefits of using genome-wide associative studies to search for new therapeutic targets.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of TechnologyReview: New Drugs for Macular Degeneration.
28.05.2010