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GD3 synthase gene therapy to improve memory and prevent neurodegeneration

GD3合酶基因疗法可改善记忆力并预防神经退行性变

基本信息

批准号：
8164474
负责人：
MICHAEL P MCDONALD
金额：
$ 30.66万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8164474
关键词：
Adult Alzheimer&apos s Disease Amyloid Amyloid Proteins Amyloid beta-Protein Amyloid beta-Protein Precursor Anxiety Attenuated Binding Birth Brain Cell Death Code Data Dementia Development Disease Enzymes Evaluation Event GD3-synthase Gangliosides Gene Silencing Genes Glycolipids Goals Human Impaired cognition In Vitro Knock-out Learning Mediating Membrane Memory Memory Loss Memory impairment Modeling Mus Mutant Strains Mice Mutation National Institute of Neurological Disorders and Stroke National Institute on Aging Nerve Degeneration Neurobehavioral Manifestations Neurons Operative Surgical Procedures Oxidative Stress Pathogenesis Pathology Patients Positioning Attribute RNA Research Role Senile Plaques Sensorimotor functions Staging Testing Therapeutic Transgenes Transgenic Mice Viral Vector Work disease characteristic experience familial Alzheimer disease gene therapy improved in vivo insight knock-down mouse model mutant neuropathology neurotoxic neurotoxicity new therapeutic target novel novel strategies novel therapeutics presenilin-1 prevent research study small hairpin RNA treatment strategy vector

项目摘要

DESCRIPTION (provided by applicant): Alzheimer's disease is characterized by the aggregation of beta-amyloid (Abeta) protein in the brain, widespread neurodegeneration, and cognitive decline. Our work focuses on amelioration of Alzheimer's pathology by reducing or eliminating GD3 synthase (GD3S), an enzyme responsible for synthesis of two of the four major brain gangliosides. Our preliminary data demonstrate that knocking out the gene that codes for GD3S (St8sia1) drastically reduces A2 aggregation and oxidative stress, and prevents memory deficits in mice carrying mutant human transgenes for amyloid precursor protein (App) and presenilin 1 (Psen1). However, GD3S is absent from birth in these mice, and they lack many of the gangliosides involved in normal development. Our goal is to understand the role of gangliosides in Alzheimer's disease and how they relate to memory impairment, the earliest cognitive symptom of the disease. The objective of this application is to determine whether knocking down GD3S using gene silencing (shRNA) is as effective as knocking out GD3S in alleviating features of Alzheimer's disease in the 5xFAD mouse model. The general hypothesis of the proposed research is that shRNA knock-down of GD3S will successfully reduce plaque formation and prevent neurodegeneration and memory impairments in adult mutant mice. We have already made three viral- vector-mediated GD3S-shRNA constructs that reduce GD3S expression ~80 percent and persist in the brain. In the proposed experiments, shRNA constructs will be administered to 5xFAD and control mice. Spatial memory will be assessed, as well as control tests for anxiety and sensorimotor function. Post-mortem analyses will assess Alzheimer- related neuropathology and cell death. Successfully reducing amyloid burden, cell death, and memory impairment in the transgenic mice may provide insight into new treatment strategies for Alzheimer's disease--treatments that could reduce or prevent dementia in Alzheimer patients. PUBLIC HEALTH RELEVANCE: The proposed experiments will test the effects of a novel genetic therapy, rAAV.GD3S.shRNA, on memory and Alzheimer-related neuropathology. The use of this vector represents not only a novel treatment strategy, but a novel therapeutic target for Alzheimer's disease. These experiments are consistent with the stated goals of National Institute on Aging and National Institute of Neurological Disorders and Stroke.

描述（由申请人提供）：阿尔茨海默病的特征是β-淀粉样蛋白（Abeta）在脑中聚集、广泛的神经变性和认知能力下降。我们的工作重点是通过减少或消除GD 3合酶（GD 3S）来改善阿尔茨海默病的病理学，GD 3S是一种负责合成四种主要脑神经节苷脂中的两种的酶。我们的初步数据表明，敲除编码GD 3S（St 8 sia 1）的基因可显著降低A2聚集和氧化应激，并防止携带淀粉样前体蛋白（App）和早老素1（Psen 1）突变人类转基因小鼠的记忆缺陷。然而，GD 3S在这些小鼠中从出生起就不存在，并且它们缺乏参与正常发育的许多神经节苷脂。我们的目标是了解神经节苷脂在阿尔茨海默病中的作用，以及它们与记忆障碍（该疾病最早的认知症状）的关系。本申请的目的是确定在5xFAD小鼠模型中，使用基因沉默（shRNA）敲除GD 3S是否与敲除GD 3S一样有效地减轻阿尔茨海默病的特征。这项研究的一般假设是，GD 3S的shRNA敲低将成功减少斑块形成，并防止成年突变小鼠的神经退行性变和记忆障碍。我们已经制造了三种病毒载体介导的GD 3S-shRNA构建体，其将GD 3S表达降低约80%并在脑中持续存在。在所提出的实验中，shRNA构建体将被给予5xFAD和对照小鼠。将评估空间记忆，以及焦虑和感觉运动功能的控制测试。尸检分析将评估阿尔茨海默病相关的神经病理学和细胞死亡。成功地减少转基因小鼠中的淀粉样蛋白负荷、细胞死亡和记忆障碍可能为阿尔茨海默病的新治疗策略提供见解--这些治疗可以减少或预防阿尔茨海默病患者的痴呆症。公共卫生关系：拟议的实验将测试一种新的遗传疗法rAAV.GD3S.shRNA对记忆和阿尔茨海默病相关神经病理学的影响。这种载体的使用不仅代表了一种新的治疗策略，而且代表了阿尔茨海默病的一种新的治疗靶点。这些实验与国家老龄化研究所和国家神经疾病和中风研究所的既定目标一致。