Catalytic immunoglobulin gene delivery in a mouse model of Alzheimer's disease: prophylactic and therapeutic applications.
Catalytic immunoglobulin gene delivery in a mouse model of Alzheimer's disease: prophylactic and therapeutic applications.
复制标题
DOI：
10.1007/s12035-014-8691-z
复制
发表时间：
2015-02
影响因子：
5.1
通讯作者：
Fukuchi, Ken-ichiro
中科院分区：
文献类型：
--
作者：
Kou, Jinghong;Yang, Junling;Lim, Jeong-Eun;Pattanayak, Abhinandan;Song, Min;Planque, Stephanie;Paul, Sudhir;Fukuchi, Ken-ichiro
淀粉样β-肽（Aβ）在脑中的积累被假设为导致阿尔茨海默病（AD）中痴呆的因果事件。Aβ疫苗接种可清除大脑中的Aβ沉积物。然而，Aβ免疫治疗可能导致T细胞和/或Fc受体介导的脑炎症，并将实质Aβ沉积物重新定位至血管，导致脑血管炎。由于催化抗体不形成稳定的免疫复合物，并且催化抗体产生的Aβ片段不太可能形成聚集体，因此Aβ特异性催化抗体可能比可逆结合抗A β抗体具有更安全的治疗特征。此外，催化抗体可以比结合抗体更有效地去除Aβ，因为单个催化抗体可以水解数千个Aβ分子。我们先前分离到了具有强Aβ水解活性的Aβ特异性催化抗体IgVL 5D3。在此，我们评估了通过重组腺相关病毒血清型9（rAAV 9）在AD小鼠模型中脑靶向IgVL 5D3基因递送的预防和治疗功效。将rAAV 9-IgVL 5D3单次注射到AD模型小鼠的右心室中，在单侧半球中产生广泛的高IgVL 5D3表达。IgVL 5D3表达在对侧半球中容易检测到，但程度小得多。在脑脊液中也证实了IgVL 5D3表达。预防性和治疗性注射rAAV 9-IgVL 5D3可降低AD模型小鼠同侧海马Aβ负荷。在实验动物中未发现脑内血管变性、血管淀粉样蛋白沉积增加、促炎细胞因子增加或浸润T细胞的证据。AAV 9介导的抗A β催化抗体脑递送可以是AD的预防和治疗选择。
Accumulation of amyloid beta-peptide (Aβ) in the brain is hypothesized to be a causal event leading to dementia in Alzheimer's disease (AD). Aβ vaccination removes Aβ deposits from the brain. Aβ immunotherapy, however, may cause T cell- and/or Fc-receptor-mediated brain inflammation and relocate parenchymal Aβ deposits to blood vessels leading to cerebral hemorrhages. Because catalytic antibodies do not form stable immune complexes and Aβ fragments produced by catalytic antibodies are less likely to form aggregates, Aβ-specific catalytic antibodies may have safer therapeutic profiles than reversibly-binding anti-Aβ antibodies. Additionally, catalytic antibodies may remove Aβ more efficiently than binding antibodies because a single catalytic antibody can hydrolyze thousands of Aβ molecules. We previously isolated Aβ-specific catalytic antibody, IgVL5D3, with strong Aβ-hydrolyzing activity. Here, we evaluated the prophylactic and therapeutic efficacy of brain-targeted IgVL5D3 gene delivery via recombinant adeno-associated virus serotype 9 (rAAV9) in an AD mouse model. One single injection of rAAV9-IgVL5D3 into the right ventricle of AD model mice yielded widespread, high expression of IgVL5D3 in the unilateral hemisphere. IgVL5D3 expression was readily detectable in the contralateral hemisphere but to a much lesser extent. IgVL5D3 expression was also confirmed in the cerebrospinal fluid. Prophylactic and therapeutic injection of rAAV9-IgVL5D3 reduced Aβ load in the ipsilateral hippocampus of AD model mice. No evidence of hemorrhages, increased vascular amyloid deposits, increased pro-inflammatory cytokines or infiltrating T cells in the brains was found in the experimental animals. AAV9-mediated anti-Aβ catalytic antibody brain delivery can be prophylactic and therapeutic options for AD.
登录
查看更多内容
影响因子：
12.4
作者：
Duque, Sandra;Joussemet, Beatrice;Barkats, Martine
通讯作者：
Barkats, Martine
影响因子：
12.4
作者：
Cearley, CN;Wolfe, JH
通讯作者：
Wolfe, JH
影响因子：
13.5
作者：
Harry, G. Jean
通讯作者：
Harry, G. Jean
影响因子：
5.3
作者：
Jimenez, Sebastian;Baglietto-Vargas, David;Vitorica, Javier
通讯作者：
Vitorica, Javier
影响因子：
64.8
作者：
Janus, C;Pearson, J;Westaway, D
通讯作者：
Westaway, D