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

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.