Small Molecule Agonists of VDAC2 to Treat Cardiac Arrhythmias and Heart Failure

Tech ID: 24411 / UC Case 2014-397-0

Summary

UCLA researchers have developed a novel small molecule as a potential therapeutic treatment for cardiac fibrillation.

Background

Aberrant Ca2+ handling in cardiomyocytes is associated with a wide range of human cardiac diseases, including heart failure and arrhythmias. To uncover novel targets implicated in aberrant Ca2+ handling, UCLA researchers developed a zebrafish model called tremblor that manifests Ca2+ extrusion defects and fibrillation-like chaotic cardiac contractions as a result ofthe loss of NCX1 sodium/calcium exchanger in cardiomyocytes.

This model was used as a phenotypic screen with a small molecule library developed at UCLA. Small molecules that restore rhythmic and coordinated cardiac contractions in tremblor in vivo were identified in this screen and used to pull down a novel mitochondrial target called VDAC2. This voltage-dependent channel protein plays a key role in maintaining Ca2+ homeostasis and may therefore be a novel drug target for atrial and ventricular fibrillation and heart failure.

Mechanistically, these compounds potentiate the Ca2+ transporting activity of VDAC2 thereby increasing the rate at which excess Ca2+ ions are transferred from the cytoplasm into the mitochondria, restoring normal rhythmic Ca2+ transients and suppressing cardiac fibrillation. The best compounds from this screen completely rescue the tremblor fibrillation phenotype in zebrafish and they have also been shown to be active in isolated adult mouse ventricular cardiomyocytes, human and mouse ES cell-derived cardiomyocytes and an initial in vivo rodent study.

The UCLA team is now working to optimize the PK/PD properties of these small molecule VDAC2 agonists and is planning to begin porcine studies in a well-characterized model of ventricular fibrillation.

Applications

Because VDAC2 is a novel drug target for atrial and ventricular fibrillation and heart failure the small molecule agonists under development at UCLA may be drug leads for all of these indications.

Advantages

  • Can effectively regulate cardiac Ca2+ homeostasis and restore cardiac function
  • No known side effects

State Of Development

In vivo studies of the present technology have been conducted.

Patent Status

Country Type Number Dated Case
Patent Cooperation Treaty Published Application WO2016100379 06/23/2016 2014-397
 

Additional Patent Pending

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Inventors

  • Chen, Jau-Nian
  • Kwon, Ohyun

Other Information

Keywords

Therapeutic, cardiac fibrillation, atrial fibrillation, small molecule, calcium homeostasis

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