To Develop a DNA Aβ42 Vaccine to Delay or Prevent Alzheimer’s Disease
Alzheimer’s disease (AD) is a devastating disease for which no treatment or intervention is currently available. AD has been strongly associated with the build-up of Amyloid beta 42 (Aβ42) in brain leading to the development of amyloid plaques (1-6).
In mouse models immunization against Aβ42 showed both, reduction of the plaques numbers and increased memory (7,8), but a clinical trial in which AD patients received Aβ42 peptide immunization was halted due to the occurrence of meningoencephalitis in 6 percent of the patients in phase II of the trial (9-11). While there was no slowing of the progression of dementia, neuropathology from the actively Aβ42 immunized AD patients showed that the treatment has lead to reduction of Aβ42 brain levels and significant reduction in plaque content (12,13), as well as positive effects on tau pathology and neurite morphology (14), and thus alternative approaches are under investigation.
A number of trials using passive immunizations had been done and is ongoing (15-20). The outcome from these trials was not as good as expected and main conclusions were that treatment was started to late in the disease (21-23). This year three major AD prevention trials have started and a positive outcome from these trials will further interest again in active anti-amyloid immunotherapies (24-27).
Aβ immunotherapy leads to increased pathology of cerebral amyloid angiopathy (CAA) in brain. The cerebral vasculare changes with age starting with fibrosis and stiffening of the arteries and arterioles which consequently leads to deposition of Aβ in the epithelial layers of the cerebral arteries (28, 29). CAA and brain microhemorrhage has been major side effects of passive Aβ immunotherapy (30, 31). AD mouse models exist to recapitulate the findings (32, 33), and as increased CAA and micorhemorrhage are major concerns for Aβ immunotherapy in patients and has to be addressed for any proposed treatment therapy.
Genetic immunization is likely a safe alternative therapy as the immune response differs from the peptide vaccination approach.
Our previous findings in which we have used a DNA Aβ42 trimer construct for immunization in mice showed a predominantly Th2-type antibody response indicative of a non- immunization time points (14, 15). Thus, the immune response following DNA immunization differs quantitatively inflammatory immune response and the disappearance of an Aβ42 specific T cell response at later and qualitatively from the immune response elicited by Aβ42 peptide immunization.
To continue with our efforts in establishing a safe therapy for AD we need to test the DNA Aβ42 immunization in larger animals, rabbit and monkey, as well as showing that the genetic immunization does not lead to the development of microhemorrhages in an aged AD mouse model. These studies are necessary to obtain an IND (Investigational New Drug) License from the FDA (Federal Drug Administration) to proceed into clinical studies with active DNA Aβ42 immunizations.
The significance of our research is to show effective anti-Aβ42 antibody production in large animals and safety of DNA Aβ42 immunotherapy in these models to proceed with vaccination in patients at risk for Alzheimer’s disease (34-40).