In situ therapeutic anti-AB delivery/adenoviral vectors

描述（由申请人提供）：淀粉样P肽（AD）免疫已成为治疗或预防阿尔茨海默病（AD）的一种新的治疗策略。在小鼠中，这种方法的有效性似乎取决于在纤维性AD免疫应答中获得高水平的抗ap抗体（Ab）的能力，或通过被动免疫递送大量的某些抗AD抗体的能力。在人类中，人们担心由于对阿尔茨海默病的免疫反应减弱或缺失，阿尔茨海默病免疫的潜在功效可能会受到损害。克服这一问题的一种方法是开发用于被动免疫的人源化抗ap抗体，然而，生产大量重组人源化抗体并非易事，只有一小部分候选治疗性抗体已被开发用于人体大规模试验。作为一种替代方法，我们建议探索重组腺病毒（Ad）载体（AdVs）在体内产生抗Ad抗体，然后在APP转基因小鼠模型中测试这些抗体，其中Ad疫苗接种已显示出有效性。此外，我们将通过两种方式评估外周与中枢神经系统抗ap抗体表达的影响。我们将比较重组抗ad AdV直接注射到大脑和外周给药，并尝试开发可全身给药但靶向中枢神经系统表达的AdV。

DESCRIPTION (provided by applicant): Amyloid P peptide (AD) immunization has emerged as a novel therapeutic strategy for the treatment or prevention of Alzheimer's disease (AD). In mice, the efficacy of this approach appears to be dependent on the ability to achieve a high level of anti-Ap antibody (Ab) in response to immunization with fibrillar AD or to deliver a large quantity of certain anti-AD Abs by passive immunization. In humans, there are concerns that the potential efficacy of AD immunization may be compromised due to a blunted or absent immune response to AD. One way to overcome this would be to develop humanized anti-Ap antibodies for passive immunization, however, production of large amounts of recombinant humanized antibodies is not trivial and only a small fraction of candidate therapeutic antibodies have been developed for large scale testing in humans. As an alternative approach we propose to explore recombinant adenoviral (Ad) vectors (AdVs) for in vivo production of anti-AD antibodies, and then to test these in an APP transgenic mouse model in which AD vaccination has been shown to have efficacy. In addition, we will evaluate the effects of peripheral versus CNS expression of the anti-Ap antibodies in two ways. We will compare direct injection of the recombinant anti-AD AdV into the brain versus peripheral administration and also attempt to develop AdVs tropic for the CNS that can be administered systemically but target expression to the CNS.