ALLOSTEROS THERAPEUTICS, INC. — Department of Health and Human Services SBIR Phase I: NHLBI

Description

DESCRIPTION provided by applicant Atrial fibrillation AF is the most common cardiac arrhythmia a condition that predisposes individuals to heart failure and stroke and is a major contributor to cardiovascular mortality There is an unmet need to treat AF and the underlying electrical and structural changes in heart There is a long unsuccessful history of ion channel blockers in AF invariably they are proarrhythmic We have identified a new target for atrial fibrillation Ca CaM dependent protein kinase II CaMKII whose hyperactivity is pro arrhythmic via multiple pathways and systems implicated in the genesis of AF and ventricular arrhythmia VA Targeting CaMKII is an innovative new paradigm treating AF while also being anti arrhythmic in ventricle In humans and mice CaMKII made hyperactivity by autophosphorylation and oxidation elicits a diastolic Ca andapos leakandapos from the sarcoplasmic reticulum via the ryanodine receptor RyR hyperphosphorylation leading to AF Atrial tissue from patients with AF is marked by elevated CaMKII activity while CaMKII inhibition prevents aberrant RyR Ca release Furthermore inhibition of the kinase with our lead compound or genetic ablation of CaMKII or its phosphorylation site on RyR blocks this chain of events and reduces the frequency of AF in mice We aim to modify our potent and selective lead compound to i reduce its rapid liver microsomal metabolism in rodents which will facilitate preclinical development toward IND and ii limit any central nervous system CNS penetration to mitigate concerns regarding CaMKII inhibition in brain Following lead optimization we will test efficacy in an established in vivo mouse model of induced AF and in an isolated rabbit heart model The Ryr R Q AF mouse model exhibits a Ca leak and susceptibility to ectopic activity reentry and AF triggered by atrial pacing Importantly these models share mechanisms with post op AF a significant inpatient indication and an achievable entry point for Allosteros Therapeutics in cardiovascular therapeutics The study will also include assay of biomarkers to assess in vivo inhibition of CaMKII and reduction in site specific phosphorylation of its targets RyR and phospholamban The Phase I work will position us for lead selection and IND enabling studies and enable us to reach metabolic and drug disposition milestones sought by investors and pharma who now recognize that CaMKII is a consensus target in AF and VA PUBLIC HEALTH RELEVANCE Atrial fibrillation is the most common cardiac arrhythmia a condition that predisposes individuals to heart failure and stroke and is a major contributor to cardiovascular mortality There is an unmet need to treat atrial fibrillation and the underlying electrical and structural changes in heart We have identified a new target Ca CaM dependent protein kinase CaMKII whose hyperactivity is associated with atrial fibrillation in human patients and in animal models We have a small molecule inhibitor of CaMKII that markedly reduces the frequency of atrial fibrillation in animal models We aim to optimize it so that it acts in the periphery and not the brain and that it is not quickly metabolized We will the test the optimized inhibitors in animal models of atrial fibrillation