Discovery of Novel Drugs for Alzheimer's Disease,

描述(申请人提供)：这个项目的目的是开发一种基因转移程序来修复或替换认知受损个体的神经递质功能。基本的前提是，将基因转移到大脑将保护神经元免受损伤，并抵消与损伤和年龄相关的衰退相关的记忆缺陷。基因转移治疗神经系统疾病的潜力很大，但在认真考虑将这项技术投入临床应用之前，仍有大量的技术和理论问题需要解决。在这项应用中，安全和有效的非病毒基因转移系统将被研究，就像在大鼠的隔膜中一样。最近，我们的实验室和其他几个实验室在提高阳离子脂质粒递送系统在体内的转染效率方面取得了进展。剩下的挑战包括对大鼠鼻中隔内基因表达谱的全面表征，胆碱能疗效的证明，以及毒性的缺乏。我们基于二硫键合成了一种新的阳离子脂质，它能够在体外和体内转染神经细胞和神经胶质细胞。我们的结果提出了一些假说，包括：1)通过减小载体的颗粒大小，可以增加隔区基因的表达，这应该会增加载体系统的分布，降低相关的毒性；以及2)非病毒介导的神经生长因子在隔区的转基因表达将增加胆碱能神经元的大小，恢复老年动物突触前海马胆碱能功能。

DESCRIPTION (provided by applicant): The aim of this project is to develop a gene transfer procedure to repair or replace neurotransmitter function in cognitively impaired individuals. The underlying premise is that gene transfer to the brain will protect against neuronal damage as well as counteract memory related deficits associated with lesions and age-related decline. The therapeutic potential of gene transfer for neurological disease is promising, yet substantial technical and theoretical problems remain to be solved before this technology can be seriously considered for clinical application. In this application, safe and efficient non-viral gene transfer systems will be studied as in the rat septum. Progress has recently been made to improve transfection efficiency of cationic lipid-plasmid delivery systems in vivo in our laboratories and several others. Challenges remaining include a full characterization of the in vivo gene expression profile in the rat septum, demonstration of cholinergic efficacy, and lack of toxicity. We have synthesized a new cationic lipid based on a disulfide approach that is capable of transfecting neuronal and glia cells in vitro and in vivo. Our results suggest some hypotheses that will be addressed in this grant, including: 1) that gene expression in the septum can be increased by decreasing the particle size of the vector, which should increase the distribution of the vector system and decrease the associated toxicity; and 2) that non-viral mediated transgene expression of nerve growth factor in the septum will increase the size of cholinergic neurons and restore presynaptic hippocampal cholinergic function in aged animals.