NERVOUS SYSTEM CHANNELOPATHIES: PATHOGENESIS & TREATMENT

描述(申请人提供)：本申请响应RFA RR-03-008，罕见病临床研究网络，并建议调查3种罕见的神经经络病：周期性瘫痪，非营养不良肌强直障碍和发作性共济失调。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成熟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，以培训一批以患者为导向的致力于罕见疾病的研究人员。研究调查人员与关注这些罕见疾病的患者倡导组织有着密切的联系：周期性瘫痪协会、国家共济失调基金会和肌肉营养不良协会。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GCRCs和一名生物统计学家，用于实施多中心临床试验，这将促进对假定的罕见疾病新疗法的疗效的调查。目前得到支持的3种特定目标疾病的病理生理学研究将为研究对象的分子特征提供资源，并使其有可能：(1)开始表征每种疾病的表型/自然病史；(2)设计治疗试验的结果衡量标准；(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。研究的重点是：(1)Andersen综合征，一种周期性瘫痪并伴有危及生命的心律失常，尚未确定治疗方法；(2)由钠和氯通道突变引起的非营养不良性肌强直，尚未有既定的治疗方法，也没有精心设计的临床试验；(3)发作性共济失调EA1和EA2，其治疗方法尚未确定。单独资助的细胞模型系统和动物模型都可以(或很快就会)用于这些疾病中的每一种，并可以为拟议的新治疗方法的第一阶段和第二阶段试验提供必要的临床前数据。这三种疾病是制定治疗策略的原型，用于治疗其他50多种罕见的神经经络病。它们也可能为了解可能由中枢神经系统通道突变/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.