Refinement of GM1416-a Drug to Treat Neurodegeneration

描述(申请人提供)：星形胶质细胞是神经元存活和功能所必需的。然而，每一种神经退行性疾病以及大脑和脊髓的每一次损伤都会导致星形胶质细胞的激活和增殖，这一过程被称为星形胶质细胞增生症，这对神经元的生存和功能产生了不利影响。因此，星形胶质细胞是一把双刃剑，在健康状态下支持动态平衡，但在病理条件下，它们的激活会导致神经元丢失。例如，中风后几周内形成的疤痕是由星形胶质细胞增殖引起的，星形胶质细胞增殖进一步损害神经元，阻止恢复并增加残疾。在慢性神经系统疾病中，如多发性硬化症，会出现进行性星形细胞增多症和相应的进行性神经元丢失。Garia Med，Inc.，一家致力于使用我们的专利、受专利保护的技术来治疗一系列神经退行性疾病和星形细胞瘤的生物技术公司，已经采取了这种理解的方法 根据定义，动态平衡的分子机制将确定重要的和新的治疗方法。以此为科学基石，在十多年来授予该公司科学创始人PI的联邦和基金会研究拨款的支持下，格里亚梅德已经确定了有效治疗一系列导致中枢神经系统动态平衡丧失的疾病的细胞和分子靶点。具体地说，几年前，我们证明了星形胶质细胞是中枢神经系统中主要的细胞类型之一，通过与神经元细胞表面特有的蛋白质成分接触，维持在细胞周期之外。我们最近发现了星形胶质细胞表达的受体，称为GMG，及其神经元配体NrS1，在这些细胞类型之间调节正向和反向信号，导致许多生物学行为，包括星形胶质细胞细胞周期停滞。在本申请中，我们提供数据说明这些相互作用的各个方面，并描述我们的先导化合物。此外，我们提供了证据表明，这些基于GM9-NrS1结合的化合物在体外和体内都能将神经元从程序性细胞死亡中拯救出来，并促进轴突发生。根据本文提供的初步数据，本申请的总体特定目标是优化这些化合物在体内的稳定性和中枢神经系统内靶点的饱和度。这些数据将支持Garia Med先导化合物从临床前到临床开发的过渡。

DESCRIPTION (provided by applicant): Astrocytes are essential for neuronal survival and function. Yet every neurodegenerative disease and every injury to the brain and spinal cord results in "activation" and proliferation of astrocytes, a process termed astrocytosis, which adversely affects neuronal survival and function. Thus, the astrocyte is a two-edged sword, supporting homeostasis in health, but, in pathologic conditions, their activation results in neuronal loss. As an example, the scar that forms in the weeks following stroke is caused by astrocyte proliferation, which further damages neurons, preventing recovery and increasing disability. In chronic neurological diseases, such as Multiple Sclerosis, there is a progressive astrocytosis and a corresponding progressive loss of neurons. GliaMed, Inc., a biotechnology company dedicated to using our proprietary, patent-protected technology to treat a range of neurodegenerative diseases and astrocytoma, has taken the approach that understanding The molecular mechanisms of homeostasis will, by definition, identify important and novel therapies. With this as its scientific cornerstone, and supported by more than a decade of federal and foundation research grants awarded to the Company's scientific founder, the PI on this application, GliaMed has identified both cellular and molecular targets for the effective treatment of a range of conditions that result in loss of CNS homeostasis. In specific, we demonstrated a number of years ago that astrocytes, one of the major celt types in the CNS, are sustained out of the cell cycle by contact with a protein component specific to the neuronal cell-surface. We have recently identified the astrocyte-expressed receptor, termed GMg, and its neuronal ligand, NrS1, that mediate both forward and reverse signaling between these cell types, that results in a number of biologies, including astrocyte cell-cycle arrest. In this application, we provide data elucidating aspects of these interactions, and describe our lead compounds. Further, we provide evidence that these compounds which are based on GM9-NrS1 binding, rescue neurons from programmed cell death and promote axogenesis, both in vitro and in vivo. The overall Specific Aim of this application, based on Preliminary Data provided herein, is to optimize these compounds for in vivo stability and saturation of target sites within the CNS. These data will support the transition of the GliaMed lead compounds from preclinical to clinical development.