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Mitochondrial calcium uptake enhancers for the treatment of cardiac arrhythmia

Dr Johann Schredelseker, Ludwig-Maximilians University; Maria Schweitzer, Ludwig-Maximilians University; Fabiola Wilting, Ludwig-Maximilians University

Ludwig-Maximilians University


Challenge

Cardiovascular diseases still represent the primary cause for hospitalization and death worldwide and especially arrhythmia-related incidents are still on the rise. This is in part related to limited effectiveness and major side effects of common anti-arrhythmic drugs which target ion channels in the cell membrane to suppress propagation of ectopic signals. Since they affect the cardiac action potential they are prone to pro-arrhythmic side effects. The use of antiarrhythmic drugs is thus difficult and anti-arrhythmic drugs cannot be given over longer time periods. It is thus a major endeavor of pharmacological research to establish novel saver treatment strategies for cardiac arrhythmia. Especially therapeutic strategies to suppress the initiation of arrhythmogenic signals inside cardiomyocytes are in focus for novel and safer antiarrhythmic therapies.


Technology

In cardiomyocytes, mitochondria are in close proximity to the sites were calcium required for muscle contraction is released and an intense cross-talk between mitochondria and these calcium release sites exists. We demonstrated that pharmacological enhancement of mitochondrial calcium uptake activates a cellular buffering mechanism, which prevents the occurrence of erratic calcium events during diastole. These diastolic calcium signals represent the cellular origin of ectopic depolarizations and cardiac arrhythmias. Administration of mitochondrial calcium uptake enhances in a zebrafish calcium overload model significantly suppressed cardiac fibrillation. Administration to mice carrying a mutation associated with arrhythmia in human significantly suppressed episodes of ventricular tachycardia.


Commercial Opportunity

Cardiac arrhythmia represent a major burden for global health. GlobalData estimates the 2013 sales only for atrial fibrillation at approximately $4.6 billion across the 8 major pharmaceutical markets (US, France, Germany, Italy, Spain, UK, Japan, and Canada) and the global market is estimated to grow to $16.17 billion in 2020. Though still in an experimental stage, our technology holds great promise to be developed into a therapy for cardiac arrhythmia.


Development Status

We have previously provided a proof-of-principle that enhancement of mitochondrial calcium uptake suppresses arrhythmogenesis in cardiac myocytes. We have demonstrated efficacy of these agents in a translational mouse model for cardiac arrhythmia in vivo and human iPSC-derived cardiomyocytes from an arrhythmia patient. We currently work with a set of pharmacological calcium uptake enhancers at various stages of development and currently aim to develop methods to identify further substances.


Patent Situation

We have identified a class of agents as candidate substances for the treatment of cardiac arrhythmia through activation of mitochondrial calcium uptake ranging from highly experimental substances to drugs with clinical approval for other indications. Patents for these substances have been filed and are at various stages of patenting.


Further Reading

• Shimizu, H. et al. Mitochondrial Ca2+ uptake by the voltage-dependent anion channel 2 regulates cardiac rhythmicity. Elife 4, (2015).

• Schweitzer, M. K. et al. Suppression of Arrhythmia by Enhancing Mitochondrial Ca2+ Uptake in Catecholaminergic Ventricular Tachycardia Models. JACC Basic to Transl. Sci. 2, 737–746 (2017).


 

Mitochondrial calcium uptake enhancers for the treatment of cardiac arrhythmia