Scientists at the Heart Center of the University Medical Center Göttingen have for the first time found an approach for a personalised therapy option with “gene editing” for the Noonan Syndrome. Publication in the renowned journal “Circulation“.
(umg/ mbexc) Congenital heart diseases are the most common organ defects. They occur in about one percent of newborns. A large number of genes are involved in a heart dysfunction. For many congenital heart diseases, such as Noonan Syndrome, the link between the genetic changes (mutations) and the heart malformations have not yet been fully understood. The possibilities for treatment are limited. In most cases, they are limited to attenuate the symptoms of the disease.
Scientists at the Heart Center of the University Medical Center Göttingen (UMG) and the Cluster of Excellence “Multiscale Bioimaging” (MBExC) have for the first time been able to identify the link between the underlying gene mutations and the development of heart muscle thickening (heart hypertrophy) for the congenital heart disease Noonan Syndrome. According to their findings, mutations in one gene, the LZTR1 gene, are the cause of the development of symptoms in some previously unexplained clinical cases. The gene regulates essential signaling pathways for cell differentiation and growth. Modified variants of the gene are the starting point for a clinically transferable, personalized therapy option using “gene editing”. The results were published in the renowned journal “Circulation“.
Original publication: Hanses U, Kleinsorge M, Roos L, Yigit G, Li Y, Barbarics B, El-Battrawy I, Lan H, Tiburcy M, Hindmarsh R, Lenz C, Salinas G, Diecke S, Müller C, Adham I, Altmüller J, Nürnberg P, Paul T, Zimmermann WH, Hasenfuss G, Wollnik B, Cyganek L (2020) Intronic CRISPR Repair in a Preclinical Model of Noonan Syndrome-Associated Cardiomyopathy. Circulation, 06.07.2020.
The interdisciplinary research was carried out under the project lead of Dr. Lukas Cyganek, head of the Stem Cell Unit at the UMG, and Prof. Dr. Bernd Wollnik, director of the Institute for Human Genetics at the UMG. Those involved included the Department of Cardiology and Pneumology (Director: Prof. Dr. Gerd Hasenfuß), the Department of Paediatric and Adolescent Medicine – Paediatric Cardiology, Intensive Care Medicine and Pneumology (Director: Prof. Dr. Thomas Paul) and the Institute of Pharmacology and Toxicology (Director: Prof. Dr. Wolfram-Hubertus Zimmermann) of the UMG. The research was funded by the German Research Foundation (DFG), the Collaborative Research Center 1002, the German Centre for Cardiovascular Research (DZHK), and by the Cluster of Excellence “Multiscale Bioimaging” (MBExC).
Noonan syndrome is a genetic disease that is associated with developmental disorders. Typical symptoms include growth retardation and dwarfism, facial malformations and serious heart defects. The genetic changes underlying the disease cause an overactivation of the so-called RAS-MAP kinase signaling pathway. This pathway is involved in many biological processes, e.g. cell differentiation and cell growth.
Research findings in detail
The research group led by Dr. Cyganek and Prof. Dr. Wollnik was able to identify mutations in the LZTR1 gene (leucine zipper like transcription regulator 1) as causative in two affected brothers with severe forms of hypertrophic cardiomyopathy. To this end, skin cells of the brothers were converted into induced pluripotent stem cells (iPS cells) in the cell culture dish and these were then programmed to become heart muscle cells. Using the heart muscle cells obtained in this way, the molecular and functional features of the disease could be investigated in greater detail. The cause of the overactivation of the RAS-MAP kinase signaling pathway, the pathological enlargement of the cells and the changes in the excitation-contraction coupling of the heart could be explained and a molecular signature of the disease could be constructed.
“The deciphering of the causal LZTR1 variants in both patients using state-of-the-art sequencing technologies and variant interpretation by our unique MutationMining(MM) team was the prerequisite to even consider gene correction for scientific analysis,” says Prof. Dr. Bernd Wollnik. In addition, the Göttingen researchers found out that the current drug therapy (calcium channel blockers or inhibition of the RAS-MAP kinase signalling pathway) is only partially effective against the symptoms in the heart muscle cells.
The patient-specific iPS cells of both children, which were recreated in the laboratory, responded immediately to a gene correction using CRISPR/Cas9, the so-called “gene scissors”: the signaling pathway activity normalized and the thickening of the heart muscles (hypertrophy) decreased. “The use of the iPS cell technology has enabled us to produce artificial heart muscle cells of the patients in the culture dish. They are the key to testing therapy options tailored to the individual patient using CRISPR/Cas9 gene scissors,” says Dr. Lukas Cyganek. Further research is now being carried out to determine whether the therapeutic approach using the gene scissors could also be used in the clinic involving patients.