In situ therapeutic anti-AB delivery/adenoviral vectors

描述（由申请人提供）：淀粉样蛋白P肽（AD）免疫已成为治疗或预防阿尔茨海默病（AD）的新治疗策略。在小鼠中，该方法的功效似乎取决于响应于用纤维状AD免疫而获得高水平的抗Ap抗体（Ab）或通过被动免疫递送大量某些抗AD Ab的能力。在人类中，人们担心AD免疫的潜在功效可能由于对AD的免疫应答减弱或缺失而受到损害。克服这一点的一种方法是开发用于被动免疫的人源化抗Ap抗体，然而，大量重组人源化抗体的产生并非微不足道，并且仅开发了一小部分候选治疗性抗体用于在人中进行大规模测试。作为一种替代方法，我们建议探索重组腺病毒（Ad）载体（AdVs）的抗AD抗体的体内生产，然后测试这些在APP转基因小鼠模型，其中AD疫苗接种已被证明具有疗效。此外，我们将以两种方式评价抗Ap抗体的外周相对于CNS表达的影响。我们将比较重组抗AD AdV直接注射入脑与外周给药，并尝试开发可全身给药但靶向表达至CNS的CNS嗜性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.