Intradermal DNA Aβ42 immunization via needle-less Jet injection as potential immunotherapy for Alzheimer’s disease

Abstract

Abstract The most common form of dementia found in the elderly is Alzheimer’s disease (AD) and AD progression has been strongly associated with accumulation of Amyloid beta 1–42 (Aβ42) and neurofibrillary tangles (tau) in brain. Amyloid pathology precedes tau pathology and an immune-mediated approach to reduce amyloid plaques without causing brain inflammation is highly desirable for possible clinical use. Genetic immunization, in which the immunizing agent is DNA encoding Aβ42, has great potential because the immune response to DNA delivered into the skin is generally non-inflammatory, and differs qualitatively from immune responses elicited by peptides, which are inflammatory with cellular production of IFNγ and IL-17. DNA immunization has been difficult in larger mammals and a potential barrier is the method for delivery of the DNA antigen. Over the last decade substantial progress has been made to increase the effectiveness of DNA delivery and immune responses, respectively. Recently, needless DNA Jet injection was approved by the FDA for a Zika vaccine. We are currently working on translating our established gene gun DNA immunization approach in mice into the clinically more feasible method of DNA delivery via jet injection. We have tested the Jet injector alone and in combination with electroporation in wild-type mice and New Zealand White rabbits as a large mammal. We found good antibody production and safe cellular immune responses (no inflammatory cytokines) in both species. Antibody levels and kinetics in mice and rabbits were very similar with about 30 μg of anti-Aβ antibodies after four immunizations. This study is designed to optimize DNA delivery for possible testing of the DNA Aβ42 vaccine for AD prevention in a future clinical trial.