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

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Abstract

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 proinflammatory 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.

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Acknowledgments

This work was supported in part by grants from the National Institutes of Health (AG037814, AG030399, and EY018478). We thank Dr. James Wilson at University of Pennsylvania for providing pAAV9 packaging plasmid and Ms. Linda Walter for assistance in preparation of this manuscript.

Competing Interests

Stephanie Planque and Sudhir Paul have a financial interest in Covalent Bioscience, Inc. and patents concerning catalytic antibodies. The other authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL, 61656, USA

    Jinghong Kou, Junling Yang, Jeong-Eun Lim, Abhinandan Pattanayak, Min Song & Ken-ichiro Fukuchi

  2. Chemical Immunology Research Center, Department of Pathology and Laboratory Medicine, University of Texas Houston Medical School, Houston, TX, 77030, USA

    Stephanie Planque & Sudhir Paul

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  1. Jinghong Kou
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Correspondence to Ken-ichiro Fukuchi.

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Supplemental Fig. S1

High magnification pictures of the areas indicated by the squares in Fig. 3. IgVL5D3 expression in the brain by rAAV9-IgVL5D3 injection was detected by immunohistochemistry using anti-c-Myc antibody. Cytoplasmic accumulation of IgVL5D3 in some ependymal cells in the choroid plexus (a) and neurons in the neocortex (b) and hippocampus (c) is shown. A strong neuropil staining in the neocortex (b) and hippocampus (c) is suggestive of IgVL5D3 secretion from cells. Scale bars 50 μm (a) and 200 μm (b and c) (GIF 561 kb)

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Kou, J., Yang, J., Lim, JE. et al. Catalytic Immunoglobulin Gene Delivery in a Mouse Model of Alzheimer’s Disease: Prophylactic and Therapeutic Applications. Mol Neurobiol 51, 43–56 (2015). https://doi.org/10.1007/s12035-014-8691-z

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