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，提出3种罕见神经通道病的研究：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疾病新疗法方面具有既定专业知识的临床研究人员联系起来。它将扩展NIH在实验疗法方面的一个原型培训计划，以培养一批以患者为导向、致力于罕见疾病的研究人员。研究人员与关注这些罕见疾病的患者权益组织有密切联系：周期性麻痹协会、国家共济失调基金会和肌肉萎缩症协会。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，用于开展多中心临床试验，这将促进对罕见病推定新疗法疗效的调查。目前支持的3种特定目标疾病的病理生理学研究将为受试者的分子表征提供资源，并使之成为可能：(1)开始表征每种疾病的表型/自然史；(2)制定治疗试验的结果指标；(3)评估生活质量——所有这些都是为新疗法的试点临床试验做准备。调查的重点是：(1)安徒生综合征，一种周期性瘫痪并伴有危及生命的心律失常，目前尚未确定治疗方法；(2)钠和氯离子通道突变引起的非营养不良性肌强直，目前尚无治疗方法，也没有设计良好的临床试验；(3)治疗尚未明确的发作性共济失调EA1和EA2。分别资助的细胞模型系统和动物模型已经（或即将）可用于这些疾病中的每一种，并且可以为拟议的新治疗的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50多种其他罕见神经通道病治疗策略的原型。它们也可能为理解可能由中枢神经系统通道突变/功能障碍（如偏头痛和癫痫）引起的常见疾病提供一个窗口。

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.