Gene editing for cardiomyopathies: next challenges by Professor Christian Kupatt
Short bio:
Professor Christian Kupatt – Interventional Cardiologist (PCI, Structural Heart disease) and principal investigator (preclinical studies for gene & cell therapy and gene editing)
After completing Med School (Ludwig-Maximillians-University of Munich), I joined clinical cardiology in 1991. From 1993 to 1997, I was working as scientific fellow to the Department of Physiology in Munich and the Cardiovascular Research at Brigham (Boston, USA), focusing on vascular and inflammatory components of cardiac reperfusion injury. Returning to the Cardiology Department of the LMU University Clinic, I pursued my clinical career as an interventional cardiologist, treating coronary artery disease as well as structural heart disease. Simultaneously, I established and continuously expanded a lab for large animal research of ischemic heart disease and gene/cell therapy. Instructed by treating patients presenting with acute myocardial infarction and chronic ischemic heart disease, I put emphasis on treatment of reperfusion injury via anti-microRNA agents and AAV-based gene therapy. The AAV vector platform fitted well to gene editing studies like correcting Duchenne´s muscular dystrophy (Moretti et al., Nat Med. 2020) and other forms of inherited cardiomyopathy. Additional pre-clinical animal models such as hypertrophic heart disease and ischemic heart failure are used to test molecular interventions modulating non-coding RNAs. In addition to an ERC Advanced Grant (2021), my lab is funded by the German Research Foundation (DFG) as well as by the German Centre for Cardiovascular Research (DZHK) and the Federal Ministry of Education and Research (BMBF), respectively.
Abstract:
Though gene therapy of various sorts (gene supplementation, micro RNA modulation, epigenetic modification) has not been fully exploited yet for the heart, the advent of CRISPR/Cas9 has enabled a previously utopian form of gene therapy: correction a disease-causing mutation as treatment option. The ever-growing trove of genetic data allows for precise identification of genetic errors, while an array of editing strategies have proven efficient in correcting the error in principle. Still, technical challenges hindering efficacy, permitting off-target effects and inflicting toxicity confine the breakthrough technology to selective protein knock-out strategies in patients, working mostly in the liver. Some of the technical challenges of cardiomyopathy editing and potential remedies are discussed.
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