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

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 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.

Intracranial IL-17A overexpression decreases cerebral amyloid angiopathy by upregulation of ABCA1 in an animal model of Alzheimer’s disease

“…The quantification data were expressed as a number of thioflavin S-positive blood vessels including cross/transverse, oblique and longitudinal planes per square millimeter of neocortex area. Data were expressed as mean ± SEM (Kou et al , 2015). …”

Biochemical features and antiviral activity of a monomeric catalytic antibody light‐chain 23D4 against influenza A virus

“…M any catalytic antibodies hydrolyzing vasoactive intestinal polypeptide (VIP) (1), DNA, RNA (2–4), HIV gp41 (5), HIV gp120 (6–8), factor VIII (9), Helicobacter pylori urease (10), hemagglutinin of influenza virus (11), and amyloid β (12, 13) have been reported in the past 2‐3 decades. On the other hand, anti‐idiotypic antibodies have been also developed as an enzyme mimic catalytic antibody (14, 15).…”

Intracranial delivery of interleukin-17A via adeno-associated virus fails to induce physical and learning disabilities and neuroinflammation in mice but improves glucose metabolism through AKT signaling pathway

“…Flag sequence encoding DYKDDDDK was placed at the C-terminal ends of IL-17A cDNA as a marker to distinguish it from endogenous IL-17A. The production of rAAV in capsid serotype 5 was performed as previously described (Kou et al, 2011; Kou et al, 2015). The titers of rAAVs were determined as described previously (Fukuchi et al, 2006).…”