(umg) Shortness of breath, fatigue and fluid retention are typical signs of chronic heart failure or kidney failure. Symptoms often remain unnoticed or seen as related to age, as organ organ aggravation progresses slowly. The causes of progressive organ failure in chronic diseases are so-called "epigenetic modifications", which are subsequent modifications of the basic building blocks of the genetic material of the cell: Certain genetic segments are useless due to chemical changes, such as chemical bonding of methyl groups (methylation of DNA)
Researchers at the heart of the University Medical Center Gottingen (UMG) have managed to reverse pathogenic epigenetic modifications in an animal model. The project group "ENPP3-mediated metabolism of phosphate in cardiac fibrosis" of the collaborative research center 1002 (SFB 1002) around prof. Dr. Med. Michael Zeisberg, Department of Nephrology and Rheumatology UMG, for their series of tests, the so-called CRISPR / Cas9 technology known as "gene scissors". "Instead of crossing DNA, modified technology can now be used to clean the genetic part of modification, such as rubber," says prof. Dr. Med. Michael Zeisberg. With this therapy, specific DNA methylation can be corrected even by fibroblasts, which are responsible for the course of the disease and which lie in the connective tissue. Since the fibroblasts release epigenetically altered DNA, pathogenic epigenetic modifications can even be detected in the blood. It is potentially possible to identify pathogenic epigenetic modifications in the kidney or even at the heart of a simple blood test, and then correct them with a customized therapy. This method represents a new approach to personalized treatment of cardiac insufficiency and chronic kidney disease. The results were published in the prestigious Nature Communications magazine.
"The results of this study give hope that in the future we will have another effective method of treatment, for example, cardiac insufficiency is available." This method opens a wide range of possible applications to regulate the activity of certain genes without the need to change the actual genetic sequence, "says Prof. Dr. Med. Gerd Hasenfuß, Chairman of the Heart Center and spokesman for Collaborative Research Center 1002.
STUDY IN THE DETAIL
The CRISPR / Cas method (CRISPR of Clustered Regular Interspaced Short Palindromic Repeats, Cas from CRISPR) uses a principle that helps bacteria to eliminate viral infections. The Cas9 protein, which is known from bacteria, is specifically directed to an arbitrary DNA area with a constructed probe RNA and is used there as a molecular "scissor": Cas9 cuts through the DNA twin wire at this point and makes subsequent DNA changes possible.
"For our purposes, we have changed the enzyme Cas9 in a way that allows certain segments of the gene to bind, but it no longer has the ability to cut them. Instead, the changed enzyme Cas9 is now associated with another enzyme, Tet3, which eradicates the pathogen epigenetic modification and returns normal state, "says Professor Zeisberg.
In the study, the successful application of this method in animal models was demonstrated for the first time. The researchers have shown that targeted demethylation of a single gene (e.g., Rasal1) in kidney fibroblasts is sufficient to reduce renal insufficiency. Currently, experiments are underway to make the enzyme more compact and allow for future application in patients.
University Medical Center Gettingen, Georg-August University
Department of Nephrology and Rheumatology
Univ. Dr. Michael Zeisberg, Managing Director
Phone 0551 / 39-20076, [email protected]
Xingbo Xu, Xiaoiing Tan, Bjoern Tampe, Tim Wilhelm, Melanie S. Hulshoff, Shoji Saito, Tobias Moser, Raghu Kalluri, Gerd Hasenfuss, Elisabeth M. Zeisberg, Michael Zeisberg: High fidelity CRISPR / Cas9 based on gene specific hydroxymethylation resources for gene expression and reduces renal fibrosis. ISSN 2041-1723, published on 29 August.