Thiothalidomides as neuroprotectants drugs for ALS

描述（由申请人提供）：本SBIR 1期提案的目标是从肿瘤坏死因子α（TNF-α）抑制剂库中确定用于治疗肌萎缩侧索硬化症（ALS）的先导候选药物。ALS是一种运动神经元疾病，影响成千上万的美国人，目前的药物显示出有限的疗效。对于ALS的新的有效治疗存在未满足的需求。最近的证据表明TNF-α是治疗ALS的药物靶点。在ALS小鼠模型的ALS患者血清和脊髓中TNF-α水平升高。选择性TNF-α抑制剂沙利度胺改善ALS小鼠的运动表现和脊髓存活，表明TNF α是ALS药物靶标。Phase 2 Discovery开发了一系列专利硫代沙利度胺，其抑制TNF-α的效力是沙利度胺的30倍。预计硫代沙利度胺比沙利度胺更有效地改善ALS小鼠的症状。 第2阶段发现将通过采用专有的基于ELISA的神经元损伤生物标志物，裂解的微管相关蛋白tau（C-tau）来评价硫代噻酰亚胺在ALS小鼠中的药物疗效。我们的研究表明，脊髓C-tau蛋白是ALS小鼠中ALS相关运动神经元损伤和药物疗效的客观生物标志物。与目前使用的终点相比，C-tau ELISA用于量化ALS相关神经病理学的效率、可靠性和特异性使药物发现能够更快地进行、使用更少的动物并降低成本。 所提出的研究将在ALS小鼠中采用转棒运动表现评分和C-tau生物标志物水平来确定TNF-α抑制硫代噻酰亚胺的功效。 具体目标：确定硫代噻酰亚胺对ALS小鼠的转棒运动性能、脊髓C-tau水平和脊髓TNF-α水平的影响。

DESCRIPTION (provided by applicant): The goal of this Phase 1 SBIR proposal is to identify lead drug candidates from a library of tumor necrosis factor a (TNF-alpha) inhibitors for treating amyotrophic lateral sclerosis (ALS). ALS is a motor neuron disorder that affects tens of thousands of Americans and current drugs display limited efficacy. An unmet need exists for new and effective treatments for ALS. Recent evidence identifies TNF-alpha as a drug target for treating ALS. TNF-a levels are elevated in ALS patient serum and spinal cord of ALS mouse models. The selective TNF-a inhibitor thalidomide improves motor performance and prolongs survival in ALS mice suggesting TNFa as an ALS drug target. Phase 2 Discovery has developed a family of proprietary thiothalidomides that are up to 30-fold more potent in inhibiting TNF-a compared to thalidomide. Thiothalidomides are predicted to be more potent than thalidomide for symptomatic improvement in ALS mice. Phase 2 Discovery will evaluate drug efficacy of thiothalidomides in ALS mice by employing a proprietary ELISA-based biomarker of neuronal damage, cleaved microtubule-associated protein tau (C-tau). Our studies indicate that spinal cord C-tau is an objective biomarker of ALS-associated motor neuron damage and drug efficacy in ALS mice. The efficiency, reliability and specificity of C-tau ELISA for quantifying ALS associated neuropathology allows drug discovery to proceed faster, use fewer animals and reduce costs compared to currently used endpoints. The proposed study will determine the efficacy of TNF-alpha inhibiting thiothalidomides employing rotorod motor performance scores and C-tau biomarker levels in ALS mice. SPECIFIC AIM: Determine the effect of thiothalidomides on rotorod motor performance, spinal cord C-tau levels and spinal cord TNF-alpha levels in ALS mice.