Wednesday, January 15, 2025
1/15/2025
Project Summary/Abstract Global Cerebral Ischemia (GCI) afflicts over 700,000 Americans each year and often results in permanent cognitive impairment or death. Here, we will complete IND-enabling studies for a therapeutic strategy for GCI. Our optimized peptide inhibitor of CaMKII, tatCN19o, shows effective and potent neuroprotection in animal models of GCI that closely mimic the most relevant human conditions: cardiopulmonary resuscitation (CPR) after cardiac arrest in mice or after ventricular fibrillation in pigs. When our CaMKII inhibitors were injected i.v. at a clinically relevant timepoint after GCI, they provided dramatic improvement over therapeutic hypothermia alone (the current standard of care); after combination with therapeutic hypothermia, only residual and barely detectable neuronal cell death was seen. Neuroprotection manifested on the anatomical, synaptic, and behavioral level. Target validation has been done using mutant mice with impaired CaMKII signaling. Target engagement has been characterized by biochemical and structural studies. This current lead compound has been optimized for potency (ki of 0.1 nM) and selectivity (>100,000x compared to the most closely related kinases). Intellectual property protection for tatCN19o is in place. The tatCN19o peptide is a tight-binding active kinase inhibitor that only engages the CaMKII fraction that remains hyperactivated after ischemic insult. These features enable optimal efficacy at an extremely low dose (0.01 mg/kg i.v.). TatCN19o is a cell- and blood-brain- barrier –penetrating 30mer peptide that is readily soluble in water or saline and highly stable in lyophilized or solubilized formulation (to be further characterized here). Current data suggest a favorable safety profile (also to be further characterized here), including lack effects on memory. These characteristics enable straightforward preparation of an injectable for clinical use in humans. Notably, tatCN19o inhibits rodent and human CaMKII equally well. Phase I of this project achieved the proposed key preclinical milestones for tatCN19o, including: characterize binding kinetics of dissociation from target, establish a quantitative method for detection in plasma, and evaluate pharmacokinetics in safety species. To enable testing in humans, this SBIR project will conduct studies required for a successful IND application, including (1) an in vivo extension of our in vitro characterization from Phase I, (2) formulation development, (3) pivotal safety studies, and (4) regulatory document preparation. The results of this proposal will serve as critical components of an IND application to the FDA, in preparation for a Phase I clinical trial and ultimately commercialization. Our Pre-IND meeting is planned for the end of year 1. The clinical/market potential for tatCN19o as a GCI therapeutic is detailed in the Commercialization Plan.
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