U01NS117284

Saracatinib and 1400W Counteract Nerve Agents-Induced Long-Term Neurotoxicity - Abstract

Chemical warfare nerve agents (CWNA) are increasingly used to attack civilians worldwide. The sarin attacks in Tokyo and Syria, as well as the VX attack in Malaysia and England, prove the real threat of CWNA. CWNA exposure impacts human health globally, but we lack effective treatment for survivors. Until recently, preventing acute death due to CWNA exposure was a top priority. However, addressing the long-term effects is also crucial given that survivors of sarin attacks, though hospitalized and treated with conventional therapy, developed seizures and cognitive, motor, and psychological impairments.

Like organophosphates (OP), CWNAs are cholinesterase inhibitors and potent seizurogenics. In animal models, acute CWNA or OP exposure induces status epilepticus (SE) and other cholinergic symptoms. The current medical countermeasures (MCM - atropine, oxime, and diazepam or midazolam) do not prevent long-term neurotoxicity and comorbidity, which are primarily due to persistent neuroinflammation and neurodegeneration.

Our overarching hypothesis is that neuroprotectants, in combination with MCM, will effectively counteract NA-induced long-term neurotoxicity and restore brain function. We propose two novel neuroprotectants: saracatinib (SAR/AZD0530, a SRC kinase inhibitor) and 1400W (an inducible NO synthase inhibitor). Both demonstrated significant neuroprotective and disease-modifying effects in kainate (KA) and DFP (a soman surrogate) rat models of chronic epilepsy. Both were tested in humans for other indications, and no adverse effects were reported. Histology of brain sections from animal models confirmed that the test drugs significantly reduced neuroinflammation and neurodegeneration, the most common features of CWNA exposure that follows SE.

We had administered both drugs (separately) and the MCM after DFP/KA/soman exposure in animals to mimic an "after field evacuation and in-hospital" scenario (FOA). As expected, MCM alone did not prevent DFP/KA-induced neurodegeneration, seizures, and neurobehavioral deficits. When neuroprotectant was administered as a follow-on therapy, we could mitigate DFP/KA/soman-induced brain pathology, which provides the proof-of-concept for the neuroprotective strategy for a CWNA exposure scenario.

We will optimize both SAR and 1400W in rat DFP and soman models and validate in G. pig (soman) and rat VX models and determine the efficacy of single or combination of both drugs in mitigating neuropathology and behavioral deficits (Specific Aims 1-3). We will conduct non-GLP PK/PD-toxicity studies and initiate drug development (SA 4) for intended use in humans (FOA). We will employ unbiased long-term video-EEG studies to quantify seizures and epileptiform spikes, and conduct MRI/PET scan, stereology to determine neuronal loss, and multiplex assay for neuroinflammatory cytokines. We will conduct a battery of behavioral tests at various time-points.

This research addresses the CounterACT mission, i.e., "to foster and support research and development of new and improved therapeutics to mitigate the health effects of chemical threats." The lead compound will move forward for FDA approval.

Iowa State University Of Science And Technology

(1) TO SUPPORT EXTRAMURAL RESEARCH FUNDED BY THE NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE (NINDS) INCLUDING: BASIC RESEARCH THAT EXPLORES THE FUNDAMENTAL STRUCTURE AND FUNCTION OF THE BRAIN AND THE NERVOUS SYSTEM, RESEARCH TO UNDERSTAND THE CAUSES AND ORIGINS OF PATHOLOGICAL CONDITIONS OF THE NERVOUS SYSTEM WITH THE GOAL OF PREVENTING THESE DISORDERS, RESEARCH ON THE NATURAL COURSE OF NEUROLOGICAL DISORDERS, IMPROVED METHODS OF DISEASE PREVENTION, NEW METHODS OF DIAGNOSIS AND TREATMENT, DRUG DEVELOPMENT, DEVELOPMENT OF NEURAL DEVICES, CLINICAL TRIALS, AND RESEARCH TRAINING IN BASIC, TRANSLATIONAL AND CLINICAL NEUROSCIENCE. THE INSTITUTE IS THE LARGEST FUNDER OF BASIC NEUROSCIENCE IN THE US AND SUPPORTS RESEARCH ON TOPICS INCLUDING BUT NOT LIMITED TO: DEVELOPMENT OF THE NERVOUS SYSTEM, INCLUDING NEUROGENESIS AND PROGENITOR CELL BIOLOGY, SIGNAL TRANSDUCTION IN DEVELOPMENT AND PLASTICITY, AND PROGRAMMED CELL DEATH, SYNAPSE FORMATION, FUNCTION, AND PLASTICITY, LEARNING AND MEMORY, CHANNELS, TRANSPORTERS, AND PUMPS, CIRCUIT FORMATION AND MODULATION, BEHAVIORAL AND COGNITIVE NEUROSCIENCE, SENSORIMOTOR LEARNING, INTEGRATION AND EXECUTIVE FUNCTION, NEUROENDOCRINE SYSTEMS, SLEEP AND CIRCADIAN RHYTHMS, AND SENSORY AND MOTOR SYSTEMS. IN ADDITION, THE INSTITUTE SUPPORTS BASIC, TRANSLATIONAL AND CLINICAL STUDIES ON A NUMBER OF DISORDERS OF THE NERVOUS SYSTEM INCLUDING (BUT NOT LIMITED TO): STROKE, TRAUMATIC INJURY TO THE BRAIN, SPINAL CORD AND PERIPHERAL NERVOUS SYSTEM, NEURODEGENERATIVE DISORDERS, MOVEMENT DISORDERS, BRAIN TUMORS, CONVULSIVE DISORDERS, INFECTIOUS DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, IMMUNE DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, INCLUDING MULTIPLE SCLEROSIS, DISORDERS RELATED TO SLEEP, AND PAIN. PROGRAMMATIC AREAS, WHICH ARE PRIMARILY SUPPORTED BY THE DIVISION OF NEUROSCIENCE, ARE ALSO SUPPORTED BY THE DIVISION OF EXTRAMURAL ACTIVITIES, THE DIVISION OF TRANSLATIONAL RESEARCH, THE DIVISION OF CLINICAL RESEARCH, THE OFFICE OF TRAINING AND WORKFORCE DEVELOPMENT, THE OFFICE OF PROGRAMS TO ENHANCE NEUROSCIENCE WORKFORCE DEVELOPMENT, AND THE OFFICE OF INTERNATIONAL ACTIVITIES. (2) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. TO UTILIZE THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM, TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.310 - Trans-NIH Research Support

National Institute of Neurological Disorders and Stroke (NNDS) [HHS - NIH]

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Ames, Iowa 500110001 United States

Single Zip Code

Countermeasures Against Chemical Threats (CounterACT): Optimization of Therapeutic Lead Compounds (U01 Clinical Trial Optional) (PAR-19-040)

Amendment Since initial award the total obligations have increased 415% from $727,305 to $3,748,151.