FIELD OF THE INVENTION

Described herein are methods and compositions related to exosomes, including extracellular vesicles for treatment and prevention of heart related disease and conditions, such as ventral arrhythmias, such as tachycardias.

BACKGROUND

Acute myocardial infarction (AMI) is experienced by more than 800,000 people in the United States annually and 75% of AMI victims survive 1 year. Approximately 300,000-350,000 of surviving patients die annually due to sudden cardiac death. Post-AMI, residual scarring of heart tissue can lead to ventricular tachycardia, which imparts a substantial risk of death. Ventricular tachycardia (VT) is a ventricular arrhythmia characterized by a fast pulse rate originating below the bundle of his and dissociated from the atria. Ventricular tachycardia may lead to Ventricular fibrillation (VF) which usually causes the person to collapse within seconds, and ends in death within minutes unless prompt corrective measures are instituted (CPR, defibrillation).

Placement of an implantable cardioverter-defibrillator (ICD) significantly reduces risk of death from VT and are implanted in more than 100,000 patients annually in the United States. Approximately 15% of patients receiving ICDs are initially treated with concomitant antiarrhythmic drug (AAD) therapy. ICDs can be very effective in terminating ventricular tachycardia, but recurrent arrhythmias and ICD shocks may cause impairment in the quality of life and are associated with an increased risk of death, heart failure, and hospitalization. Suppressive therapy, most commonly with AADs can prove problematic as pro-arrythmic, potential long term toxicity and systemic tolerance. Catheter ablation or radio frequency ablation can serve as alternatives to escalation in AAD drug therapy. However, ablation may introduce other adverse effects such as myocardial necrosis, cardiac perforation, bleeding and new arrhythmias. There is a great need in the art to develop therapeutic strategies that can reduce risk from post-MI scarring, VT and VF, and without adverse effects.

The death of cardiac myocytes is a major cause of myocardial infarct and heart failure, which may be addressed by the potential of cardiac regeneration in adult mammals. Stem cells, such as cardiosphere-derived cells (CDCs) have shown a proven therapeutic benefit by possibly tapping into the aforementioned repair and regeneration mechanisms. In addition, indirect mechanisms are responsible, where cellular exosomes (the lipid bilayer nanovesicles secreted by cells when multivesicular endosomes fuse with the plasma membrane) are central actors in the maintenance, repair and regeneration processes.

Described herein are compositions and methods related to use of exosomes, including CDC-derived exosomes for treatment and prevention of ventral arrhythmias, including tachycardias. In particular, the Inventors have discovered that extracellular vesicles, such as exosomes secreted from the cardiosphere derived cells (CDCs), are effective in reducing the propensity of the heart to lethal ventricular arrhythmias. The use of CDC-derived exosomes provides a less destructive alternative to radiofrequency ablation or cryoabalation of heart tissue, in patients susceptible to lethal ventricular arrhythmias. Focally injecting exosomes is capable of regrowing healthy heart muscle. Such result terminates the propensity to ventricular arrhythmias in subjects that have suffered a myocardial infarction.

SUMMARY OF THE INVENTION

Described herein is a method of treating a cardiac arrhythmia, including administering a therapeutically effective amount of a composition including extracellular vesicles to a subject afflicted with a cardiac arrhythmia, thereby treating the subject. In various embodiments, the method includes a subject that had a myocardial infarction. In various embodiments, the method includes subject with an implantable cardioverter-defibrillator (ICD). In various embodiments, the method includes a subject treated with initial antiarrhythmic drug (AAD) therapy. In various embodiments, the method includes a subject treated with escalating antiarrhythmic drug (AAD) therapy. In various embodiments, the method includes administering a composition comprises focal delivery at a site of isolated late potentials. In various embodiments, treating the subject comprises a reduction in the number of isolated late potentials. In various embodiments, treating the subject comprises a reduction in the isoelectric interval between late abnormal ventricular activity. In various embodiments, treating the subject comprises a decrease the incidence of inducible ventricular arrhythmias. In various embodiments, the cardiac arrhythmia comprises ventricular tachycardia. In various embodiments, the extracellular vesicles are obtained from cardiospheres, cardiosphere-derived cells (CDCs) or newt A1 cell line.

Described herein is a method of improving cardiac performance in a subject, including administering a composition including extracellular vesicles to a subject. In various embodiments, the subject is afflicted with abnormal electrical activity in the heart. In various embodiments, the subject is afflicted with slow zones of conduction in the heart. In various embodiments, the subject has heterogeneous areas of scarred myocardium. In various embodiments, the subject has had a myocardial infarction. In various embodiments, the subject has an implantable cardioverter-defibrillator (ICD). In various embodiments, administering a composition comprises focal delivery at a site of isolated late potentials.

Also described herein is a method of preventing arrhythmias in a subject including administering a composition comprising extracellular vesicles to a subject. In various embodiments, preventing arrhythmias in a subject comprises a reduction in the number of isolated late potentials. In various embodiments, preventing arrhythmias comprises a reduction in the isoelectric interval between late abnormal ventricular activity.

