Utility of novel Na Channel Slow Inactivation Enhancers in Myotonia

新型Na通道慢失活增强剂在肌强直中的效用

基本信息

批准号：
8927905
负责人：
Christoph Lossin
金额：
$ 37.17万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-19 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8927905
关键词：
Accounting Action Potentials Address Adverse effects Animal Model Animal Organ Animals Antiepileptic Agents Arrhythmia Behavior Behavioral Behavioral Assay Biological Assay Blood Brain Cardiac Cells Center for Translational Science Activities Chemical Models Clinical Clinical Trials Clinical assessments Complex Data Dental caries Development Disease Distress Drug Kinetics Drug effect disorder Electrocardiogram Enhancers Epilepsy Extramural Activities FDA approved Feeling suicidal Freezing Funding Future Genetic Models Goals Hand Health Heart High Pressure Liquid Chromatography Housekeeping Human In Vitro Label Lead Leg Letters Libraries Life Logistics Mass Spectrum Analysis Measurement Mediating Modeling Molecular Molecular Target Monitor Motion Movement Mus Muscle Muscle Cells Muscle Cramp Muscular Dystrophies Myopathy Myotonia Myotonic Disorders National Institute of Neurological Disorders and Stroke Neck Neurologic Neurons Paralysed Patients Performance Pharmaceutical Preparations Pharmacodynamics Phase Phenotype Physiological Preclinical Drug Evaluation Process Property Protein Isoforms Psyche structure Quality of life Recombinants Research Rodent Safety Science Seizures Skeletal Muscle Sodium Sodium Channel Sodium Channel Blockers Sodium Chloride Solid Structure-Activity Relationship Substance abuse problem Symptoms Testing Therapeutic Time Work arm base design drug development drug synthesis effective therapy efficacy testing experience fall risk feeding follow-up improved in vivo interest meetings member muscle pharmacology mutant novel novel therapeutics programs response voltage voltage clamp

项目摘要

DESCRIPTION (provided by applicant): Myotonia is a heritable muscle cramp disorder that robs patients of their ability to move freely and with purpose. Hands, arms, legs, neck - any willfully movable muscle - may freeze in mid-action, and normal function does not return until the same motion is repeated several times. This not only limits patients in their daily life, but i also exposes them to an incessant risk of falling, leading to mental distress and an overall reduction in the quality of life. Yet, no FDA-approved treatment exists. Instead, therapy relies on secondary actions of drugs never intended for myotonia therapy such as Mexitil, whose primary utility is the rectification of cardiac arrhythmias. Efficacy and safety of these compounds in the context of muscular hyperexcitability are hence unclear. Our long-term goal is to develop safe and effective myotonia therapies. The objective of the work proposed here is to assess the antimyotonic potential of a new therapeutic alley that involves blockade of excess sodium (Na+) channel activity, but leaves housekeeping Na+ channel functionality untouched - an approach already successfully deployed in the antiepileptic agent Vimpat. It is our hypothesis that agents mimicking Vimpat's mechanism of action but with limited access to the brain provide excellent relief from myotonia, based on the rationale that both, muscle and brain, rely on action potential initiation by voltage-gated Na+ channels. Preliminary data in myotonic mice are strongly supportive of our hypothesis. We therefore propose to establish a drug screen and drug development program based on library of compounds mechanistically related to Vimpat. Our specific aims are designed to assess these compounds' antimyotonic utility at the whole-animal, organ, cellular, and molecular level. Specifically we propose (1) to examine compound performance in animal myotonia using behavioral and electromyographic assays as well as physiological measurements (e.g., force development) in surgically isolated muscle, which will allow us to tailor-synthesize new compounds with heretofore unseen antimyotonic activity, (2) to screen candidate compounds generated in Aim #1 for central and cardiac side effects using behavioral assays and electrocardiographic means followed by HPLC/MS-based pharmacodynamic profiling, and (3) to biophysically characterize those compounds passing Aim #1 and #2, specifically their molecular action on the muscle Na+ channel Nav1.4 and their functional impact on Nav1.4 mutants associated with myotonic disorders. The novelty or our endeavor - to titer Na+ channel activity rather than altering Nav channel function per se - is expected to produce superior myotonia control without occurrence of side effects. This caries particular significance in the context of muscular hyperexcitability: our data are relevant not onl to myotonia, but to therapeutic insufficiencies in general, in particular muscle disorders where the treatment options are limited.

描述（由申请人提供）：肌强直是一种遗传性肌肉痉挛疾病，会剥夺患者自由、有目的地活动的能力。手、手臂、腿、脖子——任何可随意活动的肌肉——可能会在动作中冻结，只有重复多次相同的动作才能恢复正常功能。这不仅限制了患者的日常生活，而且使他们不断面临跌倒的风险，导致精神困扰和生活质量的整体下降。然而，尚无 FDA 批准的治疗方法。相反，治疗依赖于从未用于治疗肌强直的药物的次要作用，例如 Mexitil，其主要用途是纠正心律失常。因此，这些化合物在肌肉过度兴奋的情况下的功效和安全性尚不清楚。我们的长期目标是开发安全有效的肌强直疗法。本文提出的工作目的是评估一种新治疗方法的抗肌强直潜力，该治疗方法涉及阻断过量的钠 (Na+) 通道活性，但不影响内务 Na+ 通道功能 - 这种方法已成功应用于抗癫痫药物 Vimpat 中。我们的假设是，模仿 Vimpat 作用机制但进入大脑有限的药物可以很好地缓解肌强直，这是基于肌肉和大脑都依赖于电压门控 Na+ 通道启动动作电位的基本原理。强直小鼠的初步数据强烈支持我们的假设。因此，我们建议基于与 Vimpat 机械相关的化合物库建立药物筛选和药物开发计划。我们的具体目标是评估这些化合物在整个动物、器官、细胞和分子水平上的抗肌强直效用。具体来说，我们建议（1）使用行为和肌电图测定以及手术分离肌肉的生理测量（例如力的产生）来检查化合物在动物肌强直中的性能，这将使我们能够定制合成具有迄今为止未见的抗肌强直活性的新化合物， (2) 使用行为测定和心电图方法筛选目标 #1 中产生的候选化合物的中枢和心脏副作用，然后进行基于 HPLC/MS 的药效学分析，以及 (3)对那些通过目标 #1 和 #2 的化合物进行生物物理表征，特别是它们对肌肉 Na+ 通道 Nav1.4 的分子作用以及它们对与肌强直性疾病相关的 Nav1.4 突变体的功能影响。我们的新颖性或努力 - 滴定 Na+ 通道活性而不是改变 Nav 通道功能本身 - 预计将产生优异的肌强直控制，而不会出现副作用。这在肌肉过度兴奋的情况下具有特别重要的意义：我们的数据不仅与肌强直有关，而且与一般治疗不足有关，特别是治疗选择有限的肌肉疾病。