Development of a New DNA Vaccine for Alzheimer Disease Targeting a Wide Range of Aβ Species and Amyloidogenic Peptides

Abstract

It has recently been determined that not only Aβ oligomers, but also other Aβ species and amyloidogenic peptides are neurotoxic in Alzheimer disease (AD) and play a pivotal role in AD pathogenesis. In the present study, we attempted to develop new DNA vaccines targeting a wide range of Aβ species. For this purpose, we first performed in vitro assays with newly developed vaccines to evaluate Aβ production and Aβ secretion abilities and then chose an IgL-Aβx4-Fc-IL-4 vaccine (designated YM3711) for further studies. YM3711 was vaccinated to mice, rabbits and monkeys to evaluate anti-Aβ species antibody-producing ability and Aβ reduction effects. It was found that YM3711 vaccination induced significantly higher levels of antibodies not only to Aβ1-42 but also to AD-related molecules including AβpE3-42, Aβ oligomers and Aβ fibrils. Importantly, YM3711 significantly reduced these Aβ species in the brain of model mice. Binding and competition assays using translated YM3711 protein products clearly demonstrated that a large part of antibodies induced by YM3711 vaccination are directed at conformational epitopes of the Aβ complex and oligomers. Taken together, we demonstrate that YM3711 is a powerful DNA vaccine targeting a wide range of AD-related molecules and is worth examining in preclinical and clinical trials.

DNA Nanostructure as an Efficient Drug Delivery Platform for Immunotherapy

“…DNA nanostructure-based vaccines are promising vectors for immunizing various human diseases, including hepatitis B (Huang et al, 2017), tuberculosis (Tang et al, 2015), Alzheimer disease (Matsumoto et al, 2013), and malaria parasites (Tyagi et al, 2012). The DNA-based immunization is successful in initiating cellular and humoral immune responses without triggering immunity against the vector (King et al, 2015).…”

Alzheimer's disease vaccine development: A new strategy focusing on immune modulation

“…This immunoresponse was increased by either priming with the peptide immunogen followed by genetic vaccination (Lambracht-Washington and Rosenberg, 2012), or by co-immunization with DNA and Aβ mixtures (Liu et al, 2015). Of relevance for AD protection is that in different animal species, DNA vaccination induces antibodies directed to linear Aβ, as well as its relevant conformational epitopes and toxic oligomers (Matsumoto et al, 2013). However, in all cases genetic immunizations were started at an early age before immunosenescence.…”

Alzheimer’s disease and immunotherapy: what is wrong with clinical trials?

“…Before describing the tau-targeting therapy, we wish to introduce our newly developed anti-Aβ DNA vaccine designated YM3711. 31 …”