Mouse model of catecholaminergic polymorphic ventricular tachycardia (CPVT)

This technology is a knock-in mouse model with a mutated ryanodine receptor to study catecholaminergic polymorphic ventricular tachycardia (CPVT) and other arrhythmias.

Unmet Need: Physiological, in vivo model of cardiac arrhythmia

Atrial fibrillation (AF) and other arrhythmias contribute to hundreds of thousands of sudden deaths per year, and current treatment options have numerous side effects, including new or worsened arrhythmia. Previous research has focused on observational studies in patients with chronic AF or studies of chronic AF in animal models; thus, it has been difficult to distinguish whether observed symptoms are a cause or an effect of AF. Recently, the role of calcium leakage via the ryanodine receptor (RYR2) has been implicated in the acute triggering of AF. A physiological, in vivo model to study RYR2 and acute arrhythmia could differentiate between the causes and effects of AF and improve therapeutic development.

The Technology: Acute, inducible AF knock-in mouse with RYR2 CPVT mutation

This technology is a knock-in mouse model with a mutated human ryanodine receptor (RYR2), a calcium channel required for excitation-contraction coupling in cardiac muscle. This RYR2 mutation is known to cause CPVT, a rare and highly lethal exercise-induced acute arrhythmogenic disease. The mouse model exhibits calcium leakage and acute AF induced by burst atrial pacing, both of which were prevented by treatment with S107, a RYR2 stabilizer. Therefore, this technology can be used to understand and develop therapeutics for both ventral tachycardia (VT) and AF.

This technology has been used to study mechanisms of AF and VT, as well as to study the therapeutic effects of Rycal drugs that stabilize calcium channels.

Applications:

• Study the mechanisms of CPVT and other arrythmias
• Study heart function
• Develop and screen antiarrhythmic drugs

Advantages:

• Physiological model that mimics human disease
• Stable, readily available mouse line
• Ability to perform in vivo and ex vivo experiments
• Acute, inducible AF to study causal role of RYR2
• Can be used to study and develop therapeutics against both AF and VT

Lead Inventor:

Andrew Marks, M.D.

Related Publications:

• Xie W, Santulli G, Guo X, Gao M, Chen BX, Marks AR. “Imaging atrial arrhythmic intracellular calcium in intact heart” J Mol Cell Cardiol. 2013 Nov; 64: 120-123.

• Shan J, Xie W, Betzenhauser M, Reiken S, Chen BX, Wronska A, Marks AR. “Calcium leak through ryanodine receptors leads to atrial fibrillation in 3 mouse models of catecholaminergic polymorphic ventricular tachycardia” Circ Res. 2012 Aug; 111(6): 708-717.

• Lehnart SE, Mongillo M, Bellinger A, Lindeggar N, Chen BX, Hsueh W, Reiken S, Wronska A, Drew LJ, Ward CW, Lederer WJ, Kass RS, Morley G, Marks AR. “Leaky Ca2+ release channel/ryanodine receptor 2 causes seizures and sudden cardiac death in mice” J Clin Invest. 2008 Jun; 118(6): 2230-2245.

Tech Ventures Reference:

• IR CU20216

• Licensing Contact: Joan Martinez