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

• 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
• 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

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，它剥夺了患者自由和有目的地活动的能力。手、胳膊、腿、脖子--任何可以随意活动的肌肉--都可能在运动过程中冻结，直到重复几次相同的运动，才能恢复正常的功能。这不仅限制了患者的日常生活，而且还使他们不断面临摔倒的风险，导致精神痛苦和生活质量的整体下降。目前还没有FDA批准的治疗方法。相反，治疗依赖于 从未用于肌强直治疗的药物的次要作用，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背景下的有效性和安全性尚不清楚。我们的长期目标是开发安全有效的肌强直疗法。本文提出的工作的目的是评估一种新的治疗方法的抗肌强直潜力，该方法涉及阻断过量的钠（Na+）通道活性，但不影响管家Na+通道功能-这种方法已经成功地应用于抗癫痫药物Vimpat。我们的假设是，基于肌肉和大脑都依赖于电压门控Na+通道的动作电位启动的原理，模拟Vimpat作用机制但进入大脑受限的药物可提供肌强直的极好缓解。肌强直小鼠的初步数据强烈支持我们的假设。因此，我们建议建立一个药物筛选和药物开发计划的基础上库的化合物与Vimpat的机制。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。具体而言，我们提出（1）使用行为和肌电图测定以及生理测量（例如，力发展），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，和（3）生物药理学表征通过目标#1和#2的那些化合物，特别是它们对肌肉Na+通道Nav1.4的分子作用及其对与肌强直性疾病相关的Nav1.4突变体的功能影响。我们的新奇或奋进-滴定Na+通道活性而不是改变Nav通道功能本身-预期产生上级肌强直控制而不发生副作用。这在肌肉过度兴奋的情况下具有特别的意义：我们的数据不仅与肌强直相关，而且与一般的治疗不适应性相关，特别是治疗选择有限的肌肉疾病。