SK Channel Openers as Therapeutics for Cerebellar Ataxia

描述(申请人提供)：小脑性共济失调是一种致命的神经疾病，在美国约有15万人受到影响。目前还没有已知的预防、神经保护或对症治疗方法来治疗这种毁灭性的疾病。利用转基因小鼠模型，我们最近发现了一种新的机制，通过小脑深部神经元(DCN)的过度兴奋来启动小脑性共济失调，DCN是小脑唯一的输出途径。小电导钙激活的K+(SK)通道是DCN中放电频率的关键调节因子，在TG小鼠DCN神经元中被沉默，其自然产生的显性抑制SK亚型(SK3-1B)抑制了整个SK通道家族。出生12天的转基因小鼠出现严重的小脑性共济失调，特征是运动不协调、意向性震颤和步态异常，没有神经退行性变。这一模型与其他小脑性共济失调动物模型的研究结果强烈表明，DCN兴奋性的增加可能是导致这种疾病的重要一步。药物降低DCN兴奋性可能为小脑性共济失调提供新的治疗途径。由于SK通道在调节DCN神经元的放电频率中起关键作用，而阻断SK通道会导致放电增强，因此SK通道的开放应该会减缓DCN的放电，并改善小脑性共济失调的症状。利鲁唑是FDA批准的治疗肌萎缩侧索硬化症的药物，据报道是一种有效的SK通道开放剂。在对人类脊髓小脑性共济失调2型(SCA2)的TG小鼠模型进行的初步研究中，我们发现利鲁唑仅在治疗4天后就显著改善了运动能力。我们计划通过追求三个具体目标来扩展这些令人兴奋的初步发现： 目的1：在2种共济失调动物模型中评价利鲁唑：目的2：设计一种更有效、更有选择性的SK开放剂，与利鲁唑不同的是，它不会阻断缓慢失活的钠通道； 目的3：在2种共济失调动物模型上评价我们新的SK开放器。综上所述，这些重要的概念验证研究将有助于确定SK通道开放剂是否构成改善显性小脑性共济失调患者运动能力的新治疗方法。

DESCRIPTION (provided by applicant): Cerebellar ataxia is a lethal neurological disease, which afflicts about 150,000 people in the US. There are currently no known preventive, neuroprotective or symptomatic treatments for this devastating disease. Using a transgenic mouse model we recently identified a novel mechanism of initiation of cerebellar ataxia through hyperexcitability of the deep cerebellar neurons (DCN), the sole output pathway of the cerebellum. Small conductance Ca -activated K+ (SK) channels, key regulators of firing frequency in the DCN, were silenced in DCN neurons of Tg mice with a naturally occurring dominant-inhibitory SK isoform (SK3-1B) that suppresses the entire SK channel family. Tg mice developed severe cerebellar ataxia by the 12th day of life characterized by motor incoordination, intention tremor and gait abnormalities in the absence of neurodegeneration. This model, together with findings from other animal models for cerebellar ataxia, strongly suggests that increased DCN excitability may be an important step in the causation of this disorder. Pharmacological reduction of DCN excitability may provide a novel therapeutic approach for cerebellar ataxia. Since SK channels are critical in regulating the firing frequency of DCN neurons and their blockade causes enhanced firing, an opener of SK channels should slow down DCN firing and ameliorate the symptoms of cerebellar ataxia. Riluzole, a FDA approved drug for the therapy of amyotrophic lateral sclerosis, has been reported to be a potent SK channel opener. In a preliminary study in a Tg mouse model for human spinocerebellar ataxia type 2 (SCA2), we found that riluzole produced a dramatic improvement in motor performance after only 4 days of treatment. We plan to extend these exciting preliminary findings by pursuing 3 specific aims: Aim 1: Evaluation of riluzole in 2 animal models of ataxia; Aim 2: Design of a more potent and selective SK opener that unlike riluzole does not block slowly inactivating sodium channels; Aim 3: Evaluation of our new SK opener in 2 animal models of ataxia. Taken together these important proof-of-concept studies will help to determine whether SK channel openers constitute a new therapeutic approach to improve motor performance in dominant cerebellar ataxias.