Acute ischemic stroke (AIS) impacts 795, 000 Americans per year, leaving 90% of patients with chronic disability. Prevalent cases of AIS in the US were estimated at 6.7M in 2017, translating to 6M Americans living with permanent stroke-related disability. AIS is characterized by cerebrovascular blockage that results in the formation of a central infarct with a surrounding ischemic penumbra; the goal for neuroprotection is based on the fundamental concept of penumbral preservation (a.k.a. penumbral freezing). Currently, the only approved therapy for patients suffering from AIS is the thrombolytic agent alteplase (tPA), approved in 1996 and burdened by expansive side effects, a host of contraindications restricting eligible patient populations, and a limited therapeutic time window. Importantly, the use of mechanical thrombectomy has drastically increased in the past decade, bringing along improved clinical outcomes. It has been strongly argued that thrombectomy outcomes can be further improved by neuroprotective therapies that salvage neuronal loss in the penumbra. Our team has identified a signaling pathway that is ubiquitously activated following ischemic injury, enabling the completion of neuronal programmed cell death. Our lead neuroprotective, CM-EA1, specifically disrupts this neuronal cell death pathway. CM-EA1 is being developed to treat patients suffering from AIS, to prevent neuronal loss in the ischemic penumbra, translating to decreased disability-adjusted life years (DALYs) for patient suffering from AIS. In this application, we will demonstrate efficacy via a rigorous rat transient middle cerebral artery occlusion (tMCAO) dose-escalation study. Following these key efficacy studies, we will advance CM-EA1 to aged rodent models and large gyrencephalic animals in a Phase II development program. Our multidisciplinary team brings together a unique combination of academic, clinical and commercial expertise that will permit the development of a life-changing drug for AIS patients.
Public Health Relevance Statement: Narrative Stroke is the leading cause of acquired neurological disability and is consequently responsible for the greatest number of disability-adjusted life years (DALYs) of any neurological disorder. Despite the broad health and economic impact of acute ischemic stroke (AIS), there is currently only 1 approved drug in the US for AIS that is unfortunately indicated in only 5% of patients. Here we propose the development of a novel neuroprotective agent, CM-EA1, that acts to protect vulnerable neurons in the ischemic penumbra, translating to preserved neuronal function, and an ultimate decrease in DALYs for patients suffering from AIS.
Project Terms: Acceleration; AD dementia; Alzheimer Type Dementia; Alzheimer disease dementia; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer's; Alzheimers Dementia; Primary Senile Degenerative Dementia; primary degenerative dementia; senile dementia of the Alzheimer type; Alzheimer's Disease; Animals; Cell Death; necrocytosis; Climacteric; life change; Cytoplasm; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Eligibility Determination; Eligibility; Protocol Screening; Fibrinolytic Agents; Antithrombotic Agents; Antithrombotic Drugs; Fibrinolytic Drugs; Thrombolytic Agents; Thrombolytic Drugs; antithrombotic medication; antithrombotics; Freezing; Goals; Health; Industry; Infarction; infarct; Investments; Ischemia; Laboratories; Lead; Pb element; heavy metal Pb; heavy metal lead; Persons; Nerve Degeneration; Neuron Degeneration; neural degeneration; neurodegeneration; neurodegenerative; neurological degeneration; neuronal degeneration; nervous system disorder; Nervous System Diseases; Neurologic Disorders; Neurological Disorders; neurological disease; Neurons; Nerve Cells; Nerve Unit; Neural Cell; Neurocyte; neuronal; Patients; Alteplase; Recombinant Tissue Plasminogen Activator; T-Plasminogen Activator; Tissue Activator D-44; Tissue Plasminogen Activator; Tissue-Type Plasminogen Activator; t-PA; Potassium; K element; Production; Program Development; Radiology Specialty; General Radiology; Radiology; Rattus; Common Rat Strains; Rat; Rats Mammals; Rodent; Rodentia; Rodents Mammals; Signal Pathway; Signal Transduction; Cell Communication and Signaling; Cell Signaling; Intracellular Communication and Signaling; Signal Transduction Systems; Signaling; biological signal transduction; Solubility; Stroke; Apoplexy; Brain Vascular Accident; Cerebral Stroke; Cerebrovascular Apoplexy; Cerebrovascular Stroke; brain attack; cerebral vascular accident; cerebrovascular accident; stroked; strokes; Time; Translating; Work; Measures; Salvage-Tx; Salvage Therapy; Thrombectomy; Guidelines; improved; Acute; Chronic; Clinical; Phase; Neurological; Neurologic; disability; Neuroprotectants; Neuroprotective Drugs; Neuroprotective Agents; Funding; delayed rectifying potassium channel; delayed rectifier potassium channel; DRK1 potassium channel; Kv2.1 channel; Therapeutic; programs; Mechanics; mechanic; mechanical; Frequencies; American; neuron loss; nerve cell death; nerve cell loss; neuron cell death; neuron cell loss; neuron death; neuronal cell death; neuronal cell loss; neuronal death; neuronal loss; neuroprotection; neuroprotective; Animal Model; Animal Models and Related Studies; model of animal; Toxic effect; Toxicities; novel; economic cost; economic impact; Middle Cerebral Artery Occlusion; Neurological status; Neurologic status; Brain Infarction; brain infarct; Maximum Tolerated Dose; Maximal Tolerated Dose; Maximally Tolerated Dose; Modeling; response; stroke therapy; stroke treatment; treating stroke; Potassium Channel Blockers; Traumatic Brain Injury; Brain Trauma; traumatic brain damage; Adverse effects; Intervention; Intervention Strategies; interventional strategy; Ischemic Stroke; preventing; prevent; Dose; Data; Pre-Clinical Model; Preclinical Models; Reproducibility; Cell Death Induction; Rodent Model; Validation; validations; follow-up; Active Follow-up; active followup; follow up; followed up; followup; Development; developmental; neuron apoptosis; apoptosis of neuronal cells; neuronal apoptosis; neuronal cells programmed cell death; neurons programmed cell death; programmed cell death of neuronal cells by apoptosis; programmed cell death of neurons by apoptosis; Pathway interactions; pathway; pre-clinical; preclinical; cerebrovascular; cerebral vascular; cerebro-vascular; National Institute of Neurological Disorders and Stroke; NINDS; National Institute of Neurological Diseases and Stroke; DALY; disability-adjusted life years; Outcome; aged; Ischemic Penumbra; clinical relevance; clinically relevant; multidisciplinary; murine model; mouse model; FDA approved; patient population; in vitro activity; Phase I Study; phase 1 study; improved outcome; efficacy study; preservation; stroke patient; stroke model; side effect; ischemia injury; ischemic injury; preclinical assessment; pre-clinical assessment
