(umg) Shortness of breath, fatigue and fluid retention are typically symptoms of chronic cardiac or renal failure. Symptoms are usually not recognized or are associated with age because the deterioration in organ performance progresses slowly. The cause of progressive failure of organs in chronic diseases is called "epigenetic modifications", which are the following modifications in the basic building blocks of a cell's genetic material: Some gene segments become useless with chemical changes such as chemical binding of methyl groups (DNA methylation). ,
The researchers at the University Medical Center Göttingen (UMG) Heart Center managed to reverse the pathogenic epigenetic modification in an animal model. Project group Dr. med. "ENPP3 mediated phosphate metabolism in cardiac fibrosis" of the Collaborative Research Center 1002 (SFB 1002). Michael Zeisberg, Department of Nephrology and Rheumatology at UMG, CRISPR / Cas9 technology known as "gene scissors" for the test sequences. Professor Dr. "Instead of hacking the DNA, the modified technology can now be used to clean a gene part of the modification, like an eraser," he says. Michael Zeisberg. With this treatment, specific DNA methylations can be corrected even by fibroblasts in the connective tissue, which are responsible for the course of the disease. Because the fibroblasts release epigenetically modified DNA, pathogenic epigenetic modifications in the blood can be detected. It is possible to identify pathogenic epigenetic modifications in the kidneys, or even in the heart, by a simple blood test and then correct them by means of individual therapy. This method represents a new approach to personalized treatment of heart failure and chronic renal failure, and the results are published in the prestigious journal of Nature Communications.
"The results of this study, in the future, include heart failure. This method opens up a wide variety of applications to regulate the activity of individual genes without having to alter the actual genetic sequence," he says. Dr. med. Gerd Hasenfuß, President of the Heart Center and 1002 Spokesperson of the Collaborative Research Center.
The CRISPR / Cas method (CRISPR, Clustered Regular Short Palindromic Repeats, CRISPR-associated CAS) uses a principle that helps bacteria recover from viral infections. The Cas9 protein known from the bacteria is directed to a random DNA region with a specifically structured RNA probe and used as a molecular scissor: at this point Cas9 cuts the DNA double strand and makes subsequent changes to the DNA.
"For our purpose, we changed the Cas9 enzyme to allow it to bind specific gene segments, but we are no longer capable of cutting them. Instead, the altered Cas9 enzyme was combined with Tet3, a second enzyme that eliminates pathogenic epigenetic modification and restores the normal state," says Professor Zeisberg.
In the study, the successful implementation of this method in animal models has been shown for the first time. Researchers have shown that demethylation of a single gene (eg, Rasal1) in kidney fibroblasts is sufficient to alleviate the course of renal failure. At present, further experiments are underway to make the enzyme more compact and to enable future application to patients.
University of Göttingen Medical Center, Georg-August University
Department of Nephrology and Rheumatology
Univ. Dr. Michael Zeisberg, General Manager
Phone 0551 / 39-20076, [email protected]
Xingbo Xu, Xiaoying Tan, Bjoern Tampe, Tim Wilhelmi, Melanie S. Hulshoff, Shoji Saito, Tobias Moser, Raghu Kalluri, Gerd Hasenfuss; It weakens kidney fibrosis. ISSN 2041-1723, published August 29, 1990.