Engineering Calmodulin Proteins to Treat Ryanopathy-Associated Diseases
T2015-235 Engineered calmodulin-based therapeutics for the treatment of cardiovascular diseases.
While there are three ryanodine receptors responsible for the release of calcium from intracellular stores during excitation-contraction, ryanodine receptor channel 2 (RyR2) has emerged as an important target in the treatment of cardiac failure. When RyR2 channels cease to effectively regulate intracellular calcium release, spontaneous calcium oscillations can result in heart complications, such as arrhythmia, heart failure, seizures, and cognitive disorders. These medical conditions ("ryanopathies") are among the leading causes for hospitalization and death in the United States. Medications are available to control calcium release, but must be taken daily and can have undesirable side-effects. Therapies that can effectively and safely control ryanopathies are lagging and not specific enough to cure the condition. The need exists for therapeutics that significantly mitigate the effects of or completely eliminate ryanopathy-associated diseases entirely.
Researchers at The Ohio State University, led by Dr. Johnathan Davis, have engineered a series of recombinant calmodulin proteins (CaM) which could potentially be used for treatment of cardiac arrhythmia. The investigators determined that a deficiency in the N-terminal CaM-RyR2 interaction may be the cause of Catecholaminergic polymorphic ventricular tachycardia (CPVT). In a proof of concept murine model of CPVT, the addition of one of the engineered CaM protein decreased the calcium oscilliations. Based on extensive studies of the binding affinity of CaM for the ryanodine receptor in model systems including plants and mammals, specific mutations were engineered in the human calmodulin sequence to selectively alter the binding affinity to the ryanodine receptor. These recombinant proteins have the potential to correct ryanopathies including heart failure, exercise-indused cardiac arrest, cardiac hyper trophy, and related cardiac disorders.
- Treatment of ryanopathy-associated diseases including dialated/ischemic/idiopathic heart failure, ventricular arrhythmias, cardiac hypertrophy, sinoatrial node dysfunction, atrial fibrillation, and exercise-indused cardiac arrest
- Pharmaceutical development targeting heart failure, muscular dystrophy, seizures, or diabetes resulting from ryanopathy-associated diseases
- Engineered protein that can provide a broad and general method of targeting genetic and acquired defects resulting from dysfunctional ryanodine receptor channels
- Customizable compositions for treatment of a variety of deadly medical conditions caused or exacerbated by ryanopathy