Audentes is developing AT307 for the treatment of CASQ2-related Catecholaminergic Polymorphic Ventricular Tachycardia.
CASQ2-related Catecholaminergic Polymorphic Ventricular Tachycardia is an inherited disease caused by mutations in the CASQ2 gene. CASQ2 encodes a protein called calsequestrin 2, which plays a key role in the physiology of calcium release in cardiac muscle cells, and which is required to maintain normal heart rhythm.
Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is characterized by abnormal ventricular heartbeats (arrhythmias) that can cause dizziness and fainting and that can progress to cardiac arrest and sudden death. These arrhythmias are precipitated by exercise or stress, which place considerable limitations on activities of daily living, and introduce ongoing anxiety about the risk of arrhythmia into the lives of patients and their caregivers. If suspected by the treating physician, CPVT can be diagnosed by exercise electrocardiogram (ECG) testing, with confirmation of the specific gene defect through genetic testing. It is estimated that more than 6,000 people globally have CPVT caused by a mutation in CASQ2. There are additional types of CPVT caused by other gene mutations. Current treatments for ventricular tachycardia are considered inadequate for CASQ2-CPVT and there are no therapies currently approved specifically for the treatment of this disease.
The goal of adeno-associated virus-CASQ2 gene therapy for CPVT is long-term expression of calsequestrin 2 in cardiac muscle cells. By restoring CASQ2 protein levels, the heart is able to maintain a normal heartbeat rhythm. Results from a pre-clinical study of a single administration of adeno-associated virus-CASQ2 gene therapy in the R33Q knock-in mouse model of CASQ2-CPVT showed that transduction of the gene was effective, that levels of CASQ2 and certain associated proteins were restored to normal, that normal protein interactions and cellular architectures were recovered, and that the number of arrhythmic episodes was greatly reduced (Denegri et. al., Circulation, 2014). Favorable effects of adeno-associated virus-CASQ2 were demonstrated in both newborn and adult R33Q knock-in mice.
Researchers have also demonstrated that a single injection of the CASQ2 gene was sufficient to reverse the clinical characteristics of CASQ2-CPVT in a knock-out mouse model with no CASQ2 production of its own (Denegri et al, Circulation Research, 2012, Vol 110, Issue 5, Pages 663–668).
Together, these studies showed that a single adeno-associated virus-mediated transfer of the CASQ2 gene can reverse the effects of either absent or dysfunctional CASQ2 protein in mouse models of CASQ2-CPVT.