Treatment of cardiac arrhythmia via re-expression of TBX5 (gene therapy)
Scientists at the University Medical Center Göttingen found a connection between a reduced expression level of TBX5 and heart failure based on cardiac arrhythmia. The scientists in the group of Prof. Zimmermann were able to develop a gene therapy for the prevention and treatment of a ventricular heart disease and associated complications like cardiac arrhythmia and sudden cardiac death.
More than 60% of all deaths due to cardiovascular disease are represented by out-of-hospital Sudden Cardiac Death (SCD). The T-box protein 5 (TBX5) is an essential transcription factor for cardiac development, but it remains unclear whether TBX5 in adult ventricular cardiomyocytes might play an overlooked critical role for cardiac homeostasis.
Discovery: TBX5 protein abundance is significantly lower in left ventricular biopsies of patients with human ischemic heart disease (ICM) and dilated cardiomyopathies (DCM) when compared to non-failing hearts (Fig.1).
Fig.1: Low TBX5 expression level in left ventricular biopsies of ICM & DCM patients. NF: Healthy control, DCM: Dilated cardiomyopathies, ICM: Ischemic heart disease. Control expression: CASQ2: Calsequestrin (calcium-binding protein), GAPDH: Glyceraldehyde 3-phosphate dehydrogenase. Source GB1802864.7
Hypothesis: The decreased expression level of TBX5 in ventricular cardiomyocytes, plays an important role in the adult working myocardium.
Outcome: In mice, a loss of TBX5 expression results in cardiac arrhythmia, causing a lethality of 50% after 150 days. A re-expression of TBX5 is possible by inactivation of endogenous inhibitors like microRNA-10a or by enhancing the expression using e.g. CRISPR-dCas9 expression constructs. Enhancing the expression of TBX5 to physiological levels can be used for prevention or therapeutic treatment of a ventricular heart disease and associated complications such as cardiac arrhythmia and SCD (Fig.2).
Fig.2: TBX5 in vivo re-expression rescues arrhythmia phenotype in ventricular TBX5-KO mouse model. mRNA expression analysis shows physiological re-expression. Statistical analysis shows significantly lower heart rate variability in KO-RE vs KO-CT mice. KO-RE: TBX5 re-expression in vTBX5-KO mice, KO-CT: vTBX5-KO mice control. Source GB1802864.7
New therapeutic application (e.g. gene therapy) for the prevention or treatment of cardiac arrhythmia and sudden cardiac death by TBX5 re-expression to physiological levels.
A proof-of-concept for an AAV-based gene therapy was successfully performed (animal model).
We have filed a priority patent application, giving us the possibility of worldwide licensing (Applicant: Georg-August-Universität Göttingen public law foundation).
Dr. Martin Andresen