A Vitamin K analog countermeasure for organophosphate poisoning

点击翻译按钮获取中文摘要

Abstract 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