Disease Modifying Potential of Glatiramer Acetate in Huntington's disease

描述（由申请人提供）：亨廷顿病（HD）是一种遗传性、进行性神经退行性疾病，其特征为舞蹈病、运动功能障碍、认知障碍和行为障碍。纹状体内缺陷（BDNF）在神经元的存活、生长、分化和功能中起着重要作用，它与HD的发病机制有关。醋酸格拉替雷（Copaxone（R））是一种安全，耐受性良好，FDA批准的用于治疗多发性硬化症的药物。醋酸格拉替雷已被证明可以增加免疫细胞中的BDNF水平，这可能部分与其在多发性硬化症中的治疗益处有关。我们的初步研究结果表明，醋酸格拉替雷可引起WT和HD STHdh纹状体细胞和HD N171- 82 Q转基因小鼠纹状体神经元中BDNF蛋白水平的浓度依赖性增加，这提供了醋酸格拉替雷也可用于治疗HD的证据。因此，该探索性R21提案的目的是测试醋酸格拉替雷在HD转基因和基因敲入小鼠中延迟或预防疾病表型的能力（Aim 1）;并确定醋酸格拉替雷在不同剂量下对WT和HD小鼠模型的血清和不同脑区域中BDNF和亨廷顿蛋白表达水平的影响（Aim 2）。将FDA批准的药物（如醋酸格拉替雷）重新用于新的适应症（即HD），将有助于快速满足关键的未满足医疗需求。格拉替雷优良的安全性和耐受性记录 醋酸盐使其成为药物再利用的理想候选物。这些临床前研究的成功完成将为醋酸格拉替雷的临床试验提供基础。 人类HD患者。

DESCRIPTION (provided by applicant): Huntington's disease (HD) is an inherited, progressive neurodegenerative disorder characterized by chorea, movement dysfunction, cognitive impairment, and behavioral disturbances. Deficiencies in striatal (BDNF), which plays an important role in survival, growth, differentiation, and functioning of neurons, has been implicated in the pathogenesis of HD. Glatiramer acetate (Copaxone(R)) is a safe and well-tolerated, FDA-approved drug used for the treatment of multiple sclerosis. Glatiramer acetate has been shown to increase BDNF levels in immune cells, which may be partly related to its therapeutic benefit in multiple sclerosis. Our preliminary findings demonstrate that glatiramer acetate can elicit concentration-dependent increases in BDNF protein levels in both WT and HD STHdh striatal cells and in striatal neurons from HD N171-82Q transgenic mice, providing evidence that glatiramer acetate may also prove useful to treat HD. Thus, the goals of this exploratory R21 proposal are to test the ability of glatiramer acetate to delay or prevent disease phenotypes in HD transgenic and knock-in mice (Aim1); and to determine the effects of glatiramer acetate on BDNF and huntingtin expression levels in serum and in different brain regions of WT and HD mouse models at different doses (Aim 2). The repurposing of an FDA-approved drug, such as glatiramer acetate, into a new indication, i.e. HD, will facilitate a rapid path into a critical unmet medical need. The excellent safety and tolerability record of glatiramer acetate makes it an ideal candidate for drug repurposing efforts. The successful completion of these preclinical studies will provide the basis for a clinical trial testing glatiramer acetate in human HD patients.