Neuroene Therapeutics has discovered a novel class of well-tolerated, brain-penetrating, non-sedating compounds that are small analogs of Vitamin K (VK) that mimic the form of VK needed for mitochondrial and neurological health. Our VK analogs are effective in several animal models of pharmacoresistant seizures and Parkinson's disease. Our lead antiseizure drug (ASD) candidate is fast-acting, has broad-spectrum antiseizure activity in several pharmacoresistant seizure models, and is mitochondrial protective. Neuroene's clinical candidate has great potential as a fast-acting rescue agent and long-term chronic therapeutic. VK analogs are very stable in dry form at room temperature, allowing for long shelf life for stockpiling in the event of a public health emergency or bio-incident. Organophosphate agents (OPs) are used widely as pesticides, but are also potent nerve agents for chemical warfare. Foreign adversaries have stockpiles of chemical weapons and have used these agents in the past. OPs irreversibly inhibit the enzyme acetylcholinesterase. However, they have also been shown to inhibit other pathways at low doses where acetylcholinesterase is not inhibited. Oxidative stress and mitochondrial dysfunction occur at low OP doses, and it has been shown that OP compounds induce changes in mitochondrial membrane potential and inhibit mitochondrial complexes needed for ATP production. While there are several treatments for OP exposure, most have undesirable side effects and/or have a very narrow window to administer their drug. Whereas Neuroene's clinical candidate protects against mitochondrial dysfunction, a major toxicity of OP exposure, and does not target the mechanisms of the standard of care treatments. Neuroene's clinical candidate has excellent tolerability in mice, and naturally occurring VK has no upper dose limit/maximum tolerated dose. Neuroene's clinical candidate could represent a potentially superior alternative to the standard of care for OP exposure, or as an adjuvant to the standard treatment of care, by targeting an additional mechanism of action for OP-poisoning. Aim 1. Determine the PK properties of Neuroene's clinical candidate, safe dosing range and maximum tolerated dose in rats. Aim 2. Determine the ability of Neuroene's clinical candidate to ameliorate diisopropyl fluorophosphate (DFP) SE in rats. Aim 3. Determine the ability of Neuroene's clinical candidate to ameliorate soman poisoning in rats. Neuroene's clinical candidate is fast-acting, broad- spectrum, and protects mitochondria. This compound could immediately stabilize and override cascading effects due to poisoning by OPs. If successful, Neuroene's drug could be a dual-purpose ASD for acute settings and to reduce long-term sequela associated with OP poisoning. Neuroene's clinical candidate could be made widely available commercially to improve the United States' health security posture due our commercial indications for pharmacoresistant seizures, while being available during a public health emergency or bio-incident
Public Health Relevance Statement: Narrative Neuroene Therapeutics has a clinical lead antiseizure drug (ASD) that is fast-acting, broad-spectrum, well- tolerated, stable at room temperature, and protect mitochondrial and neuronal health. This compound has potential for stabilizing and overriding cascading effects due to poisoning by organophosphate (OP) nerve agents. If successful, our drug could be a dual-purpose ASD for acute settings and to reduce long-term sequela associated with OP poisoning. Neuroene's clinical candidate could be made widely available commercially to improve the United States' health security posture due our commercial indications for pharmacoresistant seizures, while being available during a public health emergency or bio-incident.
Project Terms: Acetylcholine; Acetylcholine Hydrolase; acetylcholine acetylhydrolase; choline esterase I; Acetylcholinesterase; Anticonvulsant Agent; Anticonvulsant Drugs; Anticonvulsive Agents; Anticonvulsive Drugs; seizure drug; seizure medication; Anticonvulsants; Atropine; dl-Hyoscyamine; Benzodiazepines; Benzodiazepine Compounds; Brain; Brain Nervous System; Encephalon; Chemical Warfare Agents; chemical warfare substances; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Emergency treatment; Emergency Therapy; Epilepsy; Epileptic Seizures; Epileptics; Seizure Disorder; epilepsia; epileptogenic; gamma-Aminobutyric Acid; 4-Aminobutanoic Acid; 4-Aminobutyric Acid; 4-amino-butanoic acid; Aminalon; Aminalone; GABA; γ-Aminobutyric Acid; Health; Isoflurophate; Di-isopropylphosphorofluoridate; Diisopropylfluorophosphate; Diisopropylphosphofluoridate; Fluostigmine; Lead; Pb element; heavy metal Pb; heavy metal lead; Membrane Potentials; Resting Potentials; Transmembrane Potentials; Midazolam; Mitochondria; mitochondrial; Mus; Mice; Mice Mammals; Murine; United States National Institutes of Health; NIH; National Institutes of Health; Neurons; Nerve Cells; Nerve Unit; Neural Cell; Neurocyte; neuronal; Ohio; Parkinson Disease; Paralysis Agitans; Parkinson; Primary Parkinsonism; Patients; Pesticides; Poisoning; poisoned; Posture; Production; Rattus; Common Rat Strains; Rat; Rats Mammals; Muscarinic Acetylcholine Receptor; Muscarinic Receptors; Research; research and development; Development and Research; R & D; R&D; Rodent; Rodentia; Rodents Mammals; sedative; Seizures; Soman; Status Epilepticus; Generalized Status Epilepticus; Temperature; Testing; Time; United States; Universities; Utah; Vitamin K; Work; fluorophosphate; Phosphorofluoridate; Measures; Caring; Organ; improved; Site; Acute; Chronic; Clinical; Penetration; Neurological; Neurologic; gamma-Aminobutyric Acid Receptors; GABA Receptor; Ensure; Chemicals; drug use; Drug usage; Oxidative Stress; analog; Funding; Therapeutic; Life; programs; Frequencies; Complex; Event; Oral; mitochondrial membrane; vitamin analog; neuroprotection; neuroprotective; authority; Animal Model; Animal Models and Related Studies; model of animal; Toxic effect; Toxicities; novel; organophosphate poisoning; Maximum Tolerated Dose; Maximal Tolerated Dose; Maximally Tolerated Dose; Modeling; Property; nerve agent; preventing; prevent; Dose; Organophosphates; Chemical Weapons; Dose Limiting; Dryness; Molecular Target; National Institute of Allergy and Infectious Disease; NIAID; Cognitive; Security; Adjuvant; Authorization documentation; Authorization; Permission; Enzyme Inhibition; Pathway interactions; pathway; Outcome; mitochondrial dysfunction; standard of care; standard treatment; standard care; drug candidate; public health emergency; clinical candidate; screening program; chemical countermeasure; side effect; long-term sequelae
