Study on Thalidomide as BACE1 inhibitor in Alzhiemer's disease

描述（由申请人提供）：考虑到阿尔茨海默病（AD）病例的数量庞大且不断增加，以及疾病的破坏性病程，非常需要开发靶向AD中关键病理机制的药物。持续的研究揭示了对AD背后的发病机制和分子机制的更多见解，并为疾病修饰疗法而不仅仅是对症治疗创造了更多希望。因为β-分泌酶（BACE 1）是A？代淀粉样前体蛋白（APP）加工的两个关键酶之一，其被认为是AD的病理标志物。最近的研究表明，BACE 1活性显着增加，在大脑和CSF影响AD轻度认知功能障碍（MCI）。因此，BACE 1抑制剂以及潜在的临床试验先导研究对于早期发现AD至关重要。最近，我们和其他人发现，阻断TNF信号可以通过抑制AD转基因小鼠中的BACE 1来减少淀粉样斑块和A？的产生。临床研究也证明，使用TNF融合蛋白拮抗剂Enteracept治疗1例AD患者已获得疗效。然而，Enteracept是一种融合蛋白药物，不能穿透脑血屏障（BBB），颈部周围注射可能对患者造成潜在风险。因此，我们决定通过使用TNF抑制剂沙利度胺来测试这一概念。我们的新方法是基于开发针对BACE 1的TNF 1抑制剂药物，从而提供影响特定下游途径的能力。作为这一概念的证明，我们将给予沙利度胺，以在AD受试者中合理地追求这种药物。我们认为沙利度胺可能是一种BACE 1抑制剂。公共卫生相关性：考虑到阿尔茨海默病（AD）病例的大量和不断增加的数量以及疾病的破坏性过程，非常需要开发靶向AD中关键病理机制的药物。持续的研究揭示了对AD背后的发病机制和分子机制的更多见解，并为疾病修饰疗法而不仅仅是对症治疗创造了更多希望。β-分泌酶（BACE 1）是淀粉样前体蛋白（APP）合成的两个关键酶之一，长期以来被认为是AD的病理标志。最近的发现表明，BACE 1活性在散发性AD脑样品中显著增加。与这些研究相关，我们发现轻度认知障碍（MCI）患者CSF中BACE 1酶活性水平和BACE 1蛋白水平均升高。因此，BACE 1抑制剂以及潜在的临床试验先导研究对于早期发现AD至关重要。最近，我们和其他人发现，阻断TNF信号可以通过抑制AD转基因小鼠中的BACE 1来减少淀粉样斑块和A？的产生。临床研究也证明，使用TNF融合蛋白拮抗剂Enteracept治疗1例AD患者已获得疗效。然而，Enteracept是一种融合蛋白药物，不能穿透脑血屏障（BBB），颈部周围注射可能对患者造成潜在风险。因此，我们决定通过使用TNF抑制剂沙利度胺来测试这一概念。我们的新方法是基于开发针对BACE 1的TNF 1抑制剂药物，从而提供影响特定下游途径的能力。作为这一概念的证明，我们将给予沙利度胺，以在AD受试者中合理地追求这种药物，并检验我们的假设，即沙利度胺降低CSF BACE 1和Ab，并改善AD受试者中神经元丢失的CSF神经元标志物。我们认为沙利度胺可能是一种BACE 1抑制剂。

DESCRIPTION (provided by applicant): Considering the large and increasing number of Alzheimer's disease (AD) cases and the devastating course of the disease, there is a great need for developing drugs that target critical pathologic mechanisms in AD. Continuing research has revealed additional insights into the pathogenesis and molecular mechanisms behind AD and has created more hope for disease-modifying therapies, rather than merely symptomatic treatment. Because beta-secretase (BACE1) is one of the two key enzymes in processing the amyloid precursor protein (APP) for A¿ generation, which has been considered a pathological hallmarker for AD. Recent discoveries have shown that BACE1 activity was significantly increased in the brain and CSF affected AD mild cognitive impairment (MCI). Thus, BACE1 inhibitors, as well as potential pilot studies for clinical trials, are crucial for the early detection of AD. Recently, we and others have discovered that blocking TNF signaling reduces amyloid plaques and A¿ production through inhibition of BACE1 in AD transgenic mice. The clinical study has also demonstrated that using the TNF fusion protein antagonist, Enteracept, has been beneficial to one AD case. However, Enteracept is a fusion protein drug which is not penetrable to the brain blood barrier (BBB), and peri-neck injections may carry potential risks for patients. Thus, we decided to test this notion by using the TNF inhibitor Thalidomide. Our novel approach is based on developing TNF1 inhibitor drugs that target BACE1 and, thus, provide the ability to influence specific downstream pathways. As a proof of this concept, we will administer Thalidomide to logically pursue this drug in AD subjects. We propose that Thalidomide may represent a BACE1 inhibitor. PUBLIC HEALTH RELEVANCE: Considering the large and increasing number of Alzheimer's disease (AD) cases and the devastating course of the disease, there is a great need for developing drugs that target critical pathologic mechanisms in AD. Continuing research has revealed additional insights into the pathogenesis and molecular mechanisms behind AD and has created more hope for disease-modifying therapies, rather than merely symptomatic treatment. Beta-secretase (BACE1) is one of the two key enzymes in processing the amyloid precursor protein (APP) for A¿ production, which has long been considered the pathological hallmark of AD. Recent discoveries have shown that BACE1 activity was significantly increased in sporadic AD brain samples. In correlation with these studies, we have discovered an elevation in both BACE1 enzymatic activity level and BACE1 protein level in the CSF from patients with mild cognitive impairment (MCI). Thus, BACE1 inhibitors, as well as potential pilot studies for clinical trials, are crucial for the early detection of AD. Recently, we and others have discovered that blocking TNF signaling reduces amyloid plaques and A¿ production through inhibition of BACE1 in AD transgenic mice. The clinical study has also demonstrated that using the TNF fusion protein antagonist, Enteracept, has been beneficial to one AD case. However, Enteracept is a fusion protein drug which is not penetrable to the brain blood barrier (BBB), and peri-neck injections may carry potential risks for patients. Thus, we decided to test this notion by using the TNF inhibitor Thalidomide. Our novel approach is based on developing TNF1 inhibitor drugs that target BACE1 and, thus, provide the ability to influence specific downstream pathways. As a proof of this concept, we will administer Thalidomide to logically pursue this drug in AD subjects and test our hypothesis that thalidomide decreases CSF BACE1 and Ab and improves CSF neuronal markers for neuron loss in AD subjects. We propose that Thalidomide may represent a BACE1 inhibitor.