Abeta DNA Vaccination for Alzheimers Disease: Focus on Disease Prevention

Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, 92697-4540, USA.
CNS & neurological disorders drug targets (Impact Factor: 2.63). 03/2010; 9(2):207-16. DOI: 10.2174/187152710791012080
Source: PubMed


Pre-clinical and clinical data suggest that the development of a safe and effective anti-amyloid-beta (Abeta) immunotherapy for Alzheimer's disease (AD) will require therapeutic levels of anti-Abeta antibodies, while avoiding proinflammatory adjuvants and autoreactive T cells which may increase the incidence of adverse events in the elderly population targeted to receive immunotherapy. The first active immunization clinical trial with AN1792 in AD patients was halted when a subset of patients developed meningoencephalitis. The first passive immunotherapy trial with bapineuzumab, a humanized monoclonal antibody against the end terminus of Abeta, also encountered some dose dependent adverse events during the Phase II portion of the study, vasogenic edema in 12 cases, which were significantly over represented in ApoE4 carriers. The proposed remedy is to treat future patients with lower doses, particularly in the ApoE4 carriers. Currently there are at least five ongoing anti-Abeta immunotherapy clinical trials. Three of the clinical trials use humanized monoclonal antibodies, which are expensive and require repeated dosing to maintain therapeutic levels of the antibodies in the patient. However in the event of an adverse response to the passive therapy antibody delivery can simply be halted, which may provide a resolution to the problem. Because at this point we cannot readily identify individuals in the preclinical or prodromal stages of AD pathogenesis, passive immunotherapy is reserved for those that already have clinical symptoms. Unfortunately those individuals have by that point accumulated substantial neuropathology in affected regions of the brain. Moreover, if Abeta pathology drives tau pathology as reported in several transgenic animal models, and once established if tau pathology can become self propagating, then early intervention with anti-Abeta immunotherapy may be critical for favorable clinical outcomes. On the other hand, active immunization has several significant advantages, including lower cost and the typical immunization protocol should be much less intrusive to the patient relative to passive therapy, in the advent of Abeta-antibody immune complex-induced adverse events the patients will have to receive immuno-supperssive therapy for an extended period until the anti Abeta antibody levels drop naturally as the effects of the vaccine decays over time. Obviously, improvements in vaccine design are needed to improve both the safety, as well as the efficacy of anti-Abeta immunotherapy. The focus of this review is on the advantages of DNA vaccination for anti-Abeta immunotherapy, and the major hurdles, such as immunosenescence, selection of appropriate molecular adjuvants, universal T cell epitopes, and possibly a polyepitope design based on utilizing existing memory T cells in the general population that were generated in response to childhood or seasonal vaccines, as well as various infections. Ultimately, we believe that the further refinement of our AD DNA epitope vaccines, possibly combined with a prime boost regime will facilitate translation to human clinical trials in either very early AD, or preferably in preclinical stage individuals identified by validated AD biomarkers.

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Available from: David H Cribbs
    • "Recently, due to its inherent versatility, gene-based vaccination technology may allow for greater precision in antigen presentation and immunomodulation that could lead to safer and more efficacious vaccines for AD.[11] Among many viruses being developed as vectors for the human gene therapy currently, adeno-associated virus (AAV) is one of the most promising tools because AAV is non-pathogenic, non-toxic with low immunogenicity, and allows long-term gene expression in many tissues, including non-dividing cells like neurons. "
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    ABSTRACT: The aim of this study was to explore the effect of adeno-associated virus (AAV) serotype 2 vector vaccine containing amyloid-β peptide (Aβ) 1-15 gene fragment (AAV-Aβ15) immunized mice sera on counteracting Aβ1-42 peptide toxicity towards a primary culture cortical neurons. BALB/c mice were vaccinated via the intramuscular immunization route with AAV-Aβ15. The anti-Aβ antibody titer of immunized mice sera was quantified by sandwich Enzyme-Linked ImmunoSorbent Assay. The toxicity of Aβ1-42 peptide on neurons was assessed by morphology with an inverse microscopy and cell viability was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. AAV-Aβ15 could induce an Aβ-specific immunoglobulin G (IgG) humoral immune response in /c mice the anti-Aβ antibodies were detectable at 1 month after immunization, significantly increased at 2 and 4 months after immunization, and the immunized sera could attenuate cytotoxicity of Aβ1-42 peptide on primary culture cortical neurons. The immune serum of AAV-Aβ15 could play a neuroprotective effect against Aβ1-42 peptide toxicity, which would be beneficial for Alzheimer's disease patients.
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    • "The first vaccine for Alzheimer's disease, known as AN1792, was composed of immunogenic fibrillar Aβ42 extracted from amyloid plaques and an adjuvant (SQ21). The vaccine induced the synthesis of antibodies against Aβ component in the brain of AD patients and the reduction of Aβ deposits if administered before the cerebral deposition of amyloid plaques [144]. Since the adjuvant may act as a powerful activator of Th1 lymphocytes, about 6% of immunized patients developed autoimmune meningoencephalitis that led to death in some cases [145]. "
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    ABSTRACT: Immune reactions inside the central nervous system are finely regulated, thanks to the presence of several checkpoints that have the fundamental purpose to preserve this fragile tissue form harmful events. The current knowledge on the role of neuroinflammation and neuro-immune interactions in the fields of multiple sclerosis, Alzheimer's disease and Parkinson's disease is reviewed. Moreover, a focus on the potential role of both active and passive immunotherapy is provided. Finally, we propose a common perspective, which implies that, under pathological conditions, inflammation may exert both detrimental and protective functions, depending on local factors and the timing of immune activation and shutting-off systems.
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    • "This may be particularly relevant when active or passive anti-Aβ immunotherapy is administered to elderly individuals who have substantial amyloid burden in the brain. Aβ-antibody immune complexes can initiate microglia and perivascular macrophage activation via FcRs, as well as trigger complement activation and release of inflammatory mediators, thereby potentially contributing to the adverse cerebral vascular events that have plagued the immunotherapy clinical trials [119,120]. "
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    ABSTRACT: Background: This study undertakes a systematic and comprehensive analysis of brain gene expression profiles of immune/inflammation-related genes in aging and Alzheimer's disease (AD). Methods: In a well-powered microarray study of young (20 to 59 years), aged (60 to 99 years), and AD (74 to 95 years) cases, gene responses were assessed in the hippocampus, entorhinal cortex, superior frontal gyrus, and post-central gyrus. Results: Several novel concepts emerge. First, immune/inflammation-related genes showed major changes in gene expression over the course of cognitively normal aging, with the extent of gene response far greater in aging than in AD. Of the 759 immune-related probesets interrogated on the microarray, approximately 40% were significantly altered in the SFG, PCG and HC with increasing age, with the majority upregulated (64 to 86%). In contrast, far fewer immune/inflammation genes were significantly changed in the transition to AD (approximately 6% of immune-related probesets), with gene responses primarily restricted to the SFG and HC. Second, relatively few significant changes in immune/inflammation genes were detected in the EC either in aging or AD, although many genes in the EC showed similar trends in responses as in the other brain regions. Third, immune/inflammation genes undergo gender-specific patterns of response in aging and AD, with the most pronounced differences emerging in aging. Finally, there was widespread upregulation of genes reflecting activation of microglia and perivascular macrophages in the aging brain, coupled with a downregulation of select factors (TOLLIP, fractalkine) that when present curtail microglial/macrophage activation. Notably, essentially all pathways of the innate immune system were upregulated in aging, including numerous complement components, genes involved in toll-like receptor signaling and inflammasome signaling, as well as genes coding for immunoglobulin (Fc) receptors and human leukocyte antigens I and II.
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