Nervous System Channelopathies: Pathogenesis & Treatment

描述（由申请人提供）：本申请响应RFA RR-03-008，罕见疾病临床研究网络，并提议研究3种罕见的神经系统通道病：周期性麻痹、非营养不良性肌强直性疾病和发作性共济失调。该研究计划将利用7个合作中心的优势，将研究这些疾病的分子科学家与在开发神经系统疾病新疗法方面具有专业知识的临床研究人员联系起来。它将扩展NIH实验治疗学的原型培训计划，以培训一支致力于罕见疾病的以患者为导向的研究人员队伍。研究人员与专注于这些罕见疾病的患者倡导组织有着密切的联系：周期性麻痹协会，国家共济失调基金会和肌营养不良协会。合作机构的一个特别优势是建立了全国性的基础设施，包括GCRC和一名生物统计学家，用于实施多中心临床试验，这将有助于调查推定的罕见疾病新疗法的疗效。目前得到支持的对这3种特定目标疾病的病理生理学的研究将为受试者的分子特征提供资源，并有可能：（1）开始对每种疾病的表型/自然史进行特征描述;（2）为治疗试验设计结果指标;（3）评估生活质量-所有这些都是为新治疗的试点临床试验做准备。研究的重点是：（1）Andersen综合征，一种周期性麻痹，伴有危及生命的心律失常，目前尚无治疗方法;（2）由钠和氯离子通道突变引起的非营养不良性肌强直，目前尚无确定的治疗方法，也没有精心设计的临床试验;（3）治疗尚未确定的发作性共济失调EA 1和EA 2。单独资助的细胞模型系统和动物模型都可（或很快将可）用于这些疾病中的每一种，并可为拟议的新型治疗的1期和2期试验提供必要的临床前数据。这3种疾病是开发其他50多种罕见神经通道病治疗策略的原型。它们也可能为了解可能由CNS通道突变/功能障碍引起的常见疾病（如偏头痛和癫痫）提供一个窗口。

DESCRIPTION (provided by applicant): This application responds to RFA RR-03-008, Rare Diseases Clinical Research Network and proposes the investigation of 3 rare neurological channelopathies: periodic paralysis, non-dystrophic myotonic disorders and episodic ataxia. The research plan will exploit the strengths of 7 collaborating centers to link molecular scientists studying these disorders with clinical investigators with established expertise in the development of new treatments for neurological disease. It will extend a prototype NIH training program in experimental therapeutics to train a cadre of patient-oriented-researchers committed to rare disorders. Study investigators have strong links with the patient advocacy organizations focused on these rare disorders: the Periodic Paralysis Association, the National Ataxia Foundation and the Muscular Dystrophy Association. A particular strength of the collaborating institutions is an established nationwide infrastructure, including GCRCs and a biostatistician, for the implementation of multicenter clinical trials that will facilitate investigation of the efficacy of putative new treatments for rare diseases. Currently-supported studies of the pathophysiology of the 3 specific target diseases will provide resources for molecular characterization of subjects and make it possible to: (1) begin the characterization of the phenotype/natural history of each; (2) devise outcome measures for treatment trials; (3) assess quality of life -- all in preparation for pilot clinical trials of novel treatments. The focus of investigation is on: (1) Andersen's syndrome, a periodic paralysis with associated life-threatening cardiac arrhythmias for which no treatment has been identified; (2) the nondystrophic myotonias caused by sodium and chloride channel mutations for which there is no established treatment and there have been no well-designed clinical trials; (3) the episodic ataxias EA1 and EA2 for which treatment is not yet defined. Both cellular model systems and animal models, funded separately, are (or soon will be) available for each of these disorders and can provide pre- clinical data necessary for proposed phase 1 and 2 trials of novel treatments. These 3 disorders are prototypes for the development of treatment strategies for over 50 other rare neurological channelopathies. They may also offer a window for understanding common disorders likely to be caused by CNS channel mutations/dysfunction such as migraine and epilepsy.