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）：Myotonia是一种可遗传的肌肉痉挛障碍，可剥夺患者自由运动和目的的能力。手，手臂，腿，颈部 - 任何故意可移动的肌肉 - 都可以在中部冻结，并且正常功能不会返回，直到重复相同的运动几次。这不仅限制了患者的日常生活，而且我还暴露了他们不断跌倒的风险，导致精神困扰和生活质量的总体下降。然而，尚无FDA批准的治疗。相反，治疗依靠药物的次要作用从未打算用于Myotonia疗法，例如Mexitil，其主要效用是心律不齐的纠正。因此，这些化合物在肌肉过度过度兴奋的背景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Myotonia疗法。这里提出的工作的目的是评估涉及过量钠（Na+）通道活性的新治疗巷的抗丝虫潜力，但使家政na+通道功能未触及 - 这种方法已经成功地部署在抗肌电剂VIMPAT中。我们的假设是，模仿Vimpat的作用机理的代理人，但由于有限的大脑机会，基于肌肉和大脑都依赖电压门控的Na+通道的动作潜在启动，从而提供了极大的缓解。肌发电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相关的化合物库建立药物筛查和药物开发计划。我们的特定目的旨在评估这些化合物在整个动物，器官，细胞和分子水平上的抗丝虫效用。具体而言，我们建议（1）使用行为和肌电图测定法检查动物肌瘤中的复合性能，以及在手术隔离的肌肉中的生理测量（例如，力发育），这将使我们能够通过核心效应和筛选群体效果（2）效果（2）量身定制新的化合物，以实现新的化合物，（2）心电图均值，然后是基于HPLC/MS的药效学分析，（3）以生物物理表征这些化合物通过AIM＃1和2的化合物，特别是它们对肌肉NA+通道NAV1.4的分子作用，及其对NAV1.4与肌动物疾病相关的功能影响。新颖性或我们的努力 - 滴度Na+通道活性而不是改变NAV通道函数本身 - 预计不会产生上肌肉症的控制，而不会出现副作用。这种在肌肉过度过度兴奋的背景下特别重要的意义：我们的数据与肌醇无关，而与通常的治疗不足有关，尤其是治疗方案受到限制的肌肉疾病。