Thiothalidomides as neuroprotectants drugs for ALS

描述（由申请人提供）：该1期SBIR提案的目标是从肿瘤坏死因子a （tnf - α）抑制剂文库中确定用于治疗肌萎缩性侧索硬化症（ALS）的主要候选药物。肌萎缩侧索硬化症是一种运动神经元疾病，影响着成千上万的美国人，目前的药物疗效有限。对ALS新的有效治疗方法的需求尚未得到满足。最近的证据表明tnf - α是治疗ALS的药物靶点。肌萎缩侧索硬化症患者血清和脊髓中TNF-a水平升高。选择性TNF-a抑制剂沙利度胺可改善ALS小鼠的运动表现并延长生存期，提示TNF-a可作为ALS药物靶点。Discovery公司已经开发了一系列专有的thiothalidomide，与thalidomide相比，其抑制TNF-a的效力提高了30倍。预计硫沙利度胺比沙利度胺对ALS小鼠的症状改善更有效。

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.