Nonviral A ␤ DNA vaccine therapy against Alzheimer’s disease: Long-term effects and safety

Department of Molecular Neuropathology, Tokyo Metropolitan Institute for Neuroscience, Musashidai 2-6, Fuchu, Tokyo 183-8526, Japan.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 07/2006; 103(25):9619-24. DOI: 10.1073/pnas.0600966103
Source: PubMed


It was recently demonstrated that amyloid beta (Abeta) peptide vaccination was effective in reducing the Abeta burden in Alzheimer model mice. However, the clinical trial was halted because of the development of meningoencephalitis in some patients. To overcome this problem, anti-Abeta antibody therapy and other types of vaccination are now in trial. In this study, we have developed safe and effective nonviral Abeta DNA vaccines against Alzheimer's disease. We administered these vaccines to model (APP23) mice and evaluated Abeta burden reduction. Prophylactic treatments started before Abeta deposition reduced Abeta burden to 15.5% and 38.5% of that found in untreated mice at 7 and 18 months of age, respectively. Therapeutic treatment started after Abeta deposition reduced Abeta burden to approximately 50% at the age of 18 months. Importantly, this therapy induced neither neuroinflammation nor T cell responses to Abeta peptide in both APP23 and wild-type B6 mice, even after long-term vaccination. Although it is reported that other anti-Abeta therapies have pharmacological and/or technical difficulties, nonviral DNA vaccines are highly secure and easily controllable and are promising for the treatment of Alzheimer's disease.

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    • "Cell culture reagents, including Dulbecco's modified Eagle's medium (DMEM), phosphatebuffered saline (PBS), and trypsin-EDTA, and ethidium monoazide (EMA) were purchased from Invitrogen (Carlsbad, CA). Plasmid DNA (pTarget-Ig-Aβ-Fc) containing an open reading frame of Aβ 1–42 peptide, a leader sequence of mouse Igκ, and the Fc domain of human immunoglobulin , in a 5′ and 3′ order, respectively, was constructed as previously described [26]. All other organic solvents were of analytical grade and used without further purification. "
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    ABSTRACT: Microneedle (MN)-based DNA vaccines have many advantages over conventional vaccines administered by hypodermic needles. However, an efficient strategy for delivering DNA vaccines to intradermal cells has not yet been established. Here, we report a new approach for delivering polyplex-based DNA vaccines using MN arrays coated with a pH-responsive polyelectrolyte multilayer assembly (PMA). This approach enabled rapid release of polyplex upon application to the skin. In addition to the polyplex-releasing MNs, we attempted to further maximize the vaccination by developing a polymeric carrier that targeted resident antigen presenting cells (APCs) rich in the intradermal area, as well as a DNA vaccine encoding a secretable fusion protein containing amyloid beta monomer (Aβ1-42), an antigenic determinant. The resulting vaccination system was able to successfully induce a robust humoral immune response compared to conventional subcutaneous injection with hypodermal needles. In addition, antigen challenge after immunization elicited an immediate and strong recall immune response due to immunogenic memory. These results suggest the potential utility of MN-based polyplex delivery systems for enhanced DNA vaccination.
    Journal of Controlled Release 01/2014; 179(1). DOI:10.1016/j.jconrel.2014.01.016 · 7.71 Impact Factor
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    • "In a previous study [30], we found that IgL-Aβ and IgL-Aβ-Fc DNA vaccines (listed in Fig. 1A) effectively reduced Aβ deposits in model mice without side effects such as neuroinflammation and microhemorrhages. Based on the results obtained, we produced several vaccines consisting of various combinations of Aβ, Fc and IL-4 to establish safer and more effective vaccine therapy (Fig. 1A). "
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    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.
    PLoS ONE 09/2013; 8(9):e75203. DOI:10.1371/journal.pone.0075203 · 3.23 Impact Factor
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    • "Many reports have explored the T-cell response after virus or non-virus-based vaccine against Alzheimer's. The T-cell response is very low or undetectable [38]–[40]. In this study, we have not explored the T-cell response, because our AAV vector expresses anti-Aβ-antibody, but not an antigen. "
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    ABSTRACT: We previously reported on a monoclonal antibody (mAb) that targeted amyloid beta (Aß) protein. Repeated injection of that mAb reduced the accumulation of Aß protein in the brain of human Aß transgenic mice (Tg2576). In the present study, cDNA encoding the heavy and light chains of this mAb were subcloned into an adeno-associated virus type 1 (AAV) vector with a 2A/furin adapter. A single intramuscular injection of 3.0×10(10) viral genome of these AAV vectors into C57BL/6 mice generated serum anti-Aß Ab levels up to 0.3 mg/ml. Anti-Aß Ab levels in excess of 0.1 mg/ml were maintained for up to 64 weeks. The effect of AAV administration on Aß levels in vivo was examined. A significant decrease in Aß levels in the brain of Tg2576 mice treated at 5 months (prophylactic) or 10 months (therapeutic) of age was observed. These results support the use of AAV vector encoding anti-Aß Ab for the prevention and treatment of Alzheimer's disease.
    PLoS ONE 03/2013; 8(3):e57606. DOI:10.1371/journal.pone.0057606 · 3.23 Impact Factor
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