Focal cerebral ischemia (stroke) afflicts nearly 800,000 Americans each year and often results in permanent cognitive impairment or death. Efforts in developing a cerebroprotective stroke therapy have largely resulted in disappointment: the only approved pharmacological therapy is hemolytic treatment with tissue plasminogen activator (tPA; alteplase). In this project, we will further develop our optimized CaMKII inhibitor peptide tatCN19o as a cerebroprotective stroke treatment through comparative testing within the NINDS Stroke Preclinical Assessment Network (SPAN). The 30 amino-acid peptide is selective, stable, potent, water soluble, and has excellent chemistry, manufacturing, and control (CMC) properties. Importantly, tatCN19o was highly effective in vivo in global cerebral ischemia (GCI) models in both mouse and pig (the latter unpublished), even at extremely low doses of 0.01-0.02 mg/kg i.v.. The parent compound was also effective in vivo in a mouse model of acute ischemic stroke (transient middle cerebral artery occlusion; tMCAo). Neuroprotection was seen even at the latest time points tested so far after the various ischemic/excitotoxic insults (0.5h after global cerebral ischemia; 1h after stroke model; 6h in neuronal cultures). Here, SPAN will provide rigorous, unbiased testing of tatCN19o in rodent tMCAo models for direct comparison to other candidate interventions. Several tMCAo conditions are proposed for consideration by the network: compatibility with hemolytic tPA treatment (the current standard of care) and efficacy after varied insult duration. To most appropriately represent clinical populations, we propose parallel testing in adult and older animals of both sexes.
Public Health Relevance Statement: Project Narrative Stroke afflicts nearly 800,000 Americans each year and often results in permanent cognitive impairment or death, leading to over $35 billion in annual healthcare costs in the US. This project will evaluate our lead cerebroprotective compound, tatCN19o, as an ischemic stroke therapy through comparative testing within the NINDS Stroke Preclinical Assessment Network (SPAN).
Project Terms: 21+ years old; Adult Human; adulthood; Adult; aminoacid; Amino Acids; Animals; inhibitor; aortic arch; aorta arch; Blood coagulation; Blood Clotting; Cell Death; necrocytosis; Chemistry; Clinical Trials; Cessation of life; Death; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Plasmin; Fibrinolysin; Glu-Plasmin; Protease F; Future; Germ Cells; Gametes; Germ-Line Cells; Reproductive Cells; Sex Cell; initial cell; sexual cell; Human; Modern Man; Ischemia; Lead; Pb element; heavy metal Pb; heavy metal lead; Magnetic Resonance Imaging; MR Imaging; MR Tomography; MRI; MRIs; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; NMR Imaging; NMR Tomography; Nuclear Magnetic Resonance Imaging; Zeugmatography; Marketing; Mus; Mice; Mice Mammals; Murine; Neurons; Nerve Cells; Nerve Unit; Neural Cell; Neurocyte; neuronal; Parents; parent; Patients; Peptide Hydrolases; Esteroproteases; Peptidases; Protease Gene; Proteases; Proteinases; Proteolytic Enzymes; Peptides; Alteplase; Recombinant Tissue Plasminogen Activator; T-Plasminogen Activator; Tissue Activator D-44; Tissue Plasminogen Activator; Tissue-Type Plasminogen Activator; t-PA; Rattus; Common Rat Strains; Rat; Rats Mammals; Reperfusion Injury; Ischemia-Reperfusion Injury; Reperfusion Damage; Risk; Rodent; Rodentia; Rodents Mammals; Standardization; Stroke; Apoplexy; Brain Vascular Accident; Cerebral Stroke; Cerebrovascular Apoplexy; Cerebrovascular Stroke; brain attack; cerebral vascular accident; cerebrovascular accident; stroked; strokes; Family suidae; Pigs; Suidae; Swine; porcine; suid; Testing; Time; Toxicology; Water; Hydrogen Oxide; Health Costs; Healthcare Costs; Health Care Costs; improved; Site; Acute; Clinical; Phase; Variation; Variant; Stimulus; Funding; CaM KII; CaM PK II; CaM kinase II; CaMKII; calcium-dependent CaM kinase II; calmodulin-dependent protein kinase II; Collaborations; Phase 3 Clinical Trials; phase III protocol; Phase III Clinical Trials; Therapeutic; Impaired cognition; Cognitive Disturbance; Cognitive Impairment; Cognitive decline; Cognitive function abnormal; Disturbance in cognition; cognitive dysfunction; cognitive loss; Consensus; Mechanics; mechanic; mechanical; Operative Surgical Procedures; Operative Procedures; Surgical; Surgical Interventions; Surgical Procedure; surgery; American; neuroprotection; neuroprotective; Reporting; Activase; Excision; Abscission; Extirpation; Removal; Surgical Removal; resection; Middle Cerebral Artery Occlusion; Modeling; Property; stroke therapy; stroke treatment; treating stroke; Tenecteplase; TNKase; Intervention; Intervention Strategies; interventional strategy; Cerebral Ischemia; model development; model developments; Ischemic Stroke; Coagulation Process; Clotting; Coagulation; Dose; Symptoms; in vivo; in vivo Model; Filament; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; sex; follow-up; Active Follow-up; active followup; follow up; followed up; followup; Development; developmental; safety study; National Institute of Neurological Disorders and Stroke; NINDS; National Institute of Neurological Diseases and Stroke; after stroke; poststroke; post stroke; determine efficacy; efficacy analysis; efficacy assessment; efficacy determination; efficacy examination; evaluate efficacy; examine efficacy; efficacy evaluation; excitotoxic; excitotoxicity; Population; aged; comparative; murine model; mouse model; FDA approved; standard of care; clinical risk; phase 3 trial; phase III trial; Peptide-based drug; therapeutic peptide; peptide drug; stroke model; risk for stroke; risk of stroke; stroke risk; cerebroprotective; cerebroprotection; critical injury; devastating injury; severe injury; patient enrollment; participant enrollment; preclinical assessment; pre-clinical assessment; hypertensive; pharmacologic; manufacture
