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

Abstract The amyloid hypothesis has been the main theory to explain the etiology of Alzheimer’s disease (AD) and provided potentially preventive and therapeutic targets. Although Aβ-immunotherapy holds promise for AD, its vascular complications reduce the efficacy and safety. We produced an adeno-associated virus vector encoding Aβ-specific catalytic antibody, rAAV9-IgV L 5D3, and evaluated the prophylactic and therapeutic efficacy and safety of rAAV9-IgV L 5D3 brain delivery in an AD mouse model. One single injection of rAAV9-IgV L 5D3 into the right ventricle achieved widespread, high expression of IgV L 5D3 in the right hippocampus and cerebrospinal fluid but less expression in the left hemisphere. The prophylactic and therapeutic application of rAAV9-IgV L 5D3 reduced Aβ load in the right hippocampus. The therapeutic application improved long-term but not short-term memory on the Morris water maze without increasing cerebral amyloid angiopathy, microhemorrhage, and inflammation. Brain-targeted gene delivery of Aβ-specific catalytic antibody can be a safer and more effective approach for AD prevention and treatment than conventional anti-Aβ antibodies.