Catalytic Immunoglobulin Gene Delivery in a Mouse Model of Alzheimer's Disease: Prophylactic and Therapeutic Applications

被引:18
作者
Kou, Jinghong [1 ]
Yang, Junling [1 ]
Lim, Jeong-Eun [1 ]
Pattanayak, Abhinandan [1 ]
Song, Min [1 ]
Planque, Stephanie [2 ]
Paul, Sudhir [2 ]
Fukuchi, Ken-ichiro [1 ]
机构
[1] Univ Illinois Coll Med Peoria, Dept Canc Biol & Pharmacol, Peoria, IL 61656 USA
[2] Univ Texas Houston Med Sch, Dept Pathol & Lab Med, Chem Immunol Res Ctr, Houston, TX 77030 USA
基金
美国国家卫生研究院;
关键词
Alzheimer's disease; Amyloid; Inflammation; Antibody; Adeno-associated virus; Immunotherapy; AMYLOID-BETA-PEPTIDE; SINGLE-CHAIN ANTIBODY; ADENOASSOCIATED VIRUS VECTORS; BLOOD-BRAIN-BARRIER; A-BETA; PROTEOLYTIC ANTIBODY; IMMUNIZATION; MICE; IMMUNOTHERAPY; TRANSDUCTION;
D O I
10.1007/s12035-014-8691-z
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Accumulation of amyloid beta-peptide (A beta) in the brain is hypothesized to be a causal event leading to dementia in Alzheimer's disease (AD). A beta vaccination removes A beta deposits from the brain. A beta immunotherapy, however, may cause T cell- and/or Fc-receptor-mediated brain inflammation and relocate parenchymal A beta deposits to blood vessels leading to cerebral hemorrhages. Because catalytic antibodies do not form stable immune complexes and A beta fragments produced by catalytic antibodies are less likely to form aggregates, A beta-specific catalytic antibodies may have safer therapeutic profiles than reversibly-binding anti-A beta antibodies. Additionally, catalytic antibodies may remove A beta more efficiently than binding antibodies because a single catalytic antibody can hydrolyze thousands of A beta molecules. We previously isolated A beta-specific catalytic antibody, IgV(L)5D3, with strong A beta-hydrolyzing activity. Here, we evaluated the prophylactic and therapeutic efficacy of brain-targeted IgV(L)5D3 gene delivery via recombinant adeno-associated virus serotype 9 (rAAV9) in an AD mouse model. One single injection of rAAV9-IgV(L)5D3 into the right ventricle of AD model mice yielded widespread, high expression of IgV(L)5D3 in the unilateral hemisphere. IgV(L)5D3 expression was readily detectable in the contralateral hemisphere but to a much lesser extent. IgV(L)5D3 expression was also confirmed in the cerebrospinal fluid. Prophylactic and therapeutic injection of rAAV9-IgV(L)5D3 reduced A beta load in the ipsilateral hippocampus of AD model mice. No evidence of hemorrhages, increased vascular amyloid deposits, increased proinflammatory cytokines, or infiltrating T-cells in the brains was found in the experimental animals. AAV9-mediated anti-A beta catalytic antibody brain delivery can be prophylactic and therapeutic options for AD.
引用
收藏
页码:43 / 56
页数:14
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