Refinement of GM1416-a Drug to Treat Neurodegeneration

描述（由申请人提供）：星形胶质细胞对神经元的存活和功能至关重要。然而，每一种神经退行性疾病和大脑和脊髓的每一种损伤都会导致星形胶质细胞的“激活”和增殖，这一过程称为星形胶质细胞增多症，它会对神经元的存活和功能产生不利影响。因此，星形胶质细胞是一把双刃剑，在健康状态下支持体内平衡，但在病理条件下，它们的激活导致神经元损失。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，阻止康复并增加残疾。在慢性神经系统疾病中，例如多发性硬化症，存在进行性星形细胞增多和相应的神经元进行性丧失。 GliaMed，Inc.，一家致力于使用我们专有的、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， 根据定义，内稳态的分子机制将确定重要的和新的治疗方法。以此作为其科学基石，并得到授予该公司科学创始人（本申请的PI）的十多年联邦和基金会研究赠款的支持，GliaMed已经确定了有效治疗一系列导致CNS稳态丧失的疾病的细胞和分子靶点。具体地说，我们几年前证明了星形胶质细胞，CNS中的主要细胞类型之一，通过与神经元细胞表面特异性的蛋白质组分接触而持续脱离细胞周期。我们最近已经确定了星形胶质细胞表达的受体，称为GMg，及其神经元配体，NrS 1，介导这些细胞类型之间的正向和反向信号传导，导致许多生物学，包括星形胶质细胞细胞周期阻滞。在本申请中，我们提供了阐明这些相互作用方面的数据，并描述了我们的先导化合物。此外，我们提供的证据表明，这些化合物是基于GM 9-NrS 1结合，拯救神经元程序性细胞死亡和促进轴突生成，在体外和体内。基于本文提供的初步数据，本申请的总体具体目的是优化这些化合物的体内稳定性和CNS内靶位点的饱和度。这些数据将支持GliaMed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.