Antisense Oligonucleotide Treatment for Alzheimer's Disease

描述（由申请人提供）： 阿尔茨海默病（Alzheimer's disease，AD）是一种进行性中枢神经系统（central nervous system，CNS）退行性疾病，是老年人痴呆的最常见原因。目前，估计有450万美国人患有AD，到2050年，预计将有1150万至1600万美国人患有这种疾病。学习和记忆缺陷是阿尔茨海默病的标志，淀粉样β蛋白（A？）在这些缺陷中起着关键作用。大脑中A的水平升高会导致大脑中的氧化损伤，从而导致学习和记忆缺陷。血脑屏障（BBB）中低密度脂蛋白受体相关蛋白-1（LRP-1）（A？的脑-血转运蛋白）的水平降低被假设为A？在脑中蓄积的可能机制（Zlokovic的神经血管假说）。AD的动物模型已被证明是研究AD及其可能治疗的有用工具。例如，我们和其他人已经将SAMP 8小鼠的特征描述为具有自然突变，该突变产生与年龄相关的学习和记忆障碍，这是由与年龄相关的大脑A水平增加驱动的。SAMP 8小鼠还出现Ab从脑流出减少，对脑的氧化损伤增加，并且胆碱能系统受损。所有这些AD样特征都可以通过向大脑中注射A？抗体来逆转。然而，由于给Ab抗体的问题，我们最近开发了一种反义寡核苷酸，称为OL-1，其针对A 1-42的氨基酸17-30，人和小鼠之间的同源区域。这个反义降低了A？在SAMP 8小鼠中，通过降低脑中的A水平，逆转学习和记忆缺陷，减少脑中的氧化组织损伤，并恢复BBB的A流出。然而，SAMP 8小鼠过量产生小鼠A，这就提出了反义是否能在人类中起作用的问题。过表达人APP的小鼠的可用性提供了OL-1的翻译模型。因此，我们建议确定OL-1是否是有效的AD的转基因小鼠模型，Tg 2576，过表达人类APP基因。我们假设反义寡核苷酸OL-1将改善学习和记忆，降低A？水平，改善A？从大脑穿过BBB的流出，并减少AD的Tg 2576转基因小鼠模型中的自由基损伤。我们将确定OL-1是否可以逆转13个月Tg 2576小鼠的学习和记忆缺陷，增加胆碱能张力，降低A？水平，减少斑块，逆转Tg 2576小鼠的氧化损伤，以及OL-1是否可以恢复Tg 2576小鼠的A？流出和LRP-1水平。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a progressive neurodegenerative disorder of the central nervous system (CNS) and is the most common cause of dementia in the elderly. Currently, an estimated 4.5 million Americans have AD and by the year 2050 there are projected to be 11.5 to 16 million Americans with the disease. Learning and memory deficits are the hallmark of Alzheimer's disease and amyloid beta protein (A¿) plays a key role in these deficits. Elevated brain levels of A¿ lead to oxidative damage in the brain resulting in learning and memory deficits. Reduced levels in the blood-brain-barrier (BBB) of low density lipoprotein receptor-related protein-1 (LRP-1), the brain-to-blood transporter of A¿, has been hypothesized as a possible mechanism contributing to the accumulation of A¿ in the brain (Neurovascular Hypothesis of Zlokovic). Animal models of AD have proved useful tools in the study of AD and its possible treatments. For example, we and others have characterized the SAMP8 mouse as having a natural mutation that produces an age-related impairment in learning and memory that is driven by an age-related increase in brain levels of A¿. SAMP8 mice also develop a decrease in Ab efflux from the brain, have increased oxidative damage to the brain, and an impaired cholinergic system. All of these AD-like characteristics are reversed by administration into the brain of antibody to A¿. However, due to the problems of giving antibody to Ab, we have more recently developed an antisense oligonucleotide, termed OL-1, that is directed at amino acids 17-30 of A¿1-42, a region homologous between human and mouse. This antisense lowers A¿ levels in the brain, reverses learning and memory deficits, decreases the oxidative tissue damage in the brain, and restores A¿ efflux by the BBB in SAMP8 mouse. The SAMP8 mouse, however, overproduces mouse A¿ this raises the question of whether antisense the antisense would work in humans. The availability of mice overexpressing human APP provides a translational model for OL-1. Therefore, we propose to determine whether OL-1 is effective in a transgenic mouse model of AD, the Tg2576 that overexpresses the human APP gene. We hypothesize that the antisense oligonucleotide OL-1 will improve learning and memory, decrease levels of A¿, improve efflux of A¿ from the brain across the BBB, and decrease free radical damage in the Tg2576 transgenic mouse model of AD. We will determine whether OL-1 can reverse the learning and memory deficits present in 13 month Tg2576, increase cholinergic tone, decrease A¿ levels, decrease plaque, reverse oxidative damage in the Tg2576 mice , and if OL-1can restore A¿ efflux and LRP-1 levels in Tg2576 mice.