The cardiac ryanodine receptor channel 2 (RyR2) is known as the Ca²⁺ release channel of the sarcoplasmic reticulum (SR), and is believed to be a good therapeutic target in a group of certain heart diseases, known as cardiac ryanopathies. A number of mutations in the RyR2 gene have been linked to a wide spectrum of arrhythmic heart disease. Impaired RyR2 leads to heart diseases such as congestive heart failure (CHF), catecholeaminergic polymorphic ventricular tachycardia (CPVT), arrhythmogenic right ventricular dysplasia type 2 (ARVD2), and Ca²⁺ release deficiency syndrome. Addressing dysregulated Ca²⁺ release offers an effective therapy for cardiac ryanopathies.

The Unmet Need

First line therapy for CPVT is beta-blockers. If beta-blocker therapy is ineffective, flecainide, a Na+ channel inhibitor that may also inhibit RyR2 Ca²⁺ release, may be added. Other currently available therapies, such as dantrolene, a water-insoluble small molecule hydantoin derivative, and mavacamten, a small molecule inhibitor of the cardiac myosin ATPase, have side-effects due to the off-target and non-specific effects of the drugs. Therapies that prevent the functional remodeling of RyR2 are believed to be promising new strategies for addressing Ca²⁺-dependent processes governed by diastolic SR Ca2+ leak. Currently, there are not any clinically available RyR2-specific inhibitors addressing dysregulated Ca²⁺ release.

The Technology

Researchers at The Ohio State University have developed novel chloride intracellular channel (CLIC) polypeptides and polynucleotides encoding the CLIC polypeptides useful for treating a cardiovascular disorder, a neurological disorder, or a reproductive disorder in a patient having one or more mutations at a RYR2 gene (ryanopathies) or having a ryanodine receptor 2 (RyR2)-associated disorder. The CLIC proteins (CLIC1-CLIC6) regulate diverse physiological functions and have been implicated in human diseases. CLIC4 is a mitochondrial-associated membrane Cl^- channel that modulates Ca²⁺ homeostasis and affects endoplasmic reticulum/sarcoplasmic reticulum (ER/SR)-mitochondrial Ca²⁺ transfer. The novel polynucleotides may be delivered via a viral vector, and can directly bind to RyR2 and fix the leakiness of the Ca2+ ions.