Dataset Information

MultiTEP platform-based DNA vaccines for alpha-synucleinopathies: preclinical evaluation of immunogenicity and therapeutic potency.

ABSTRACT: We have previously demonstrated that anti-beta amyloid DNA vaccine (AV-1959D) based on our proprietary MultiTEP platform technology is extremely immunogenic in mice, rabbits, and monkeys. Importantly, MultiTEP platform enables development of vaccines targeting pathological molecules involved in various neurodegenerative disorders. Taking advantage of the universality of MultiTEP platform, we developed DNA vaccines targeting 3 B-cell epitopes (amino acids [aa]85-99, aa109-126, and aa126-140) of human alpha-synuclein (h?-Syn) separately or all 3 epitopes simultaneously. All 4 DNA vaccines (1) generate high titers of anti-h?-Syn antibodies and (2) induce robust MultiTEP-specific T-helper cell responses without activation of potentially detrimental autoreactive anti-h?-Syn T-helper cells. Generated antibodies recognize misfolded h?-Syn produced by neuroblastoma cells, h?-Syn in the brain tissues of transgenic mouse strains and in the brain tissues of dementia with Lewy body cases. Based on these results, the most promising vaccine targeting 3 B-cell epitopes of h?-Syn simultaneously (PV-1950D) has been chosen for ongoing preclinical assessment in mouse models of h?-Syn with the aim to translate it to the human clinical trials.

SUBMITTER: Davtyan H

PROVIDER: S-EPMC5612893 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

MultiTEP platform-based DNA vaccines for alpha-synucleinopathies: preclinical evaluation of immunogenicity and therapeutic potency.

Davtyan Hayk H Zagorski Karen K Petrushina Irina I Kazarian Konstantin K Goldberg Natalie R S NRS Petrosyan Janet J Blurton-Jones Mathew M Masliah Eliezer E Cribbs David H DH Agadjanyan Michael G MG Ghochikyan Anahit A

Neurobiology of aging 20170810

We have previously demonstrated that anti-beta amyloid DNA vaccine (AV-1959D) based on our proprietary MultiTEP platform technology is extremely immunogenic in mice, rabbits, and monkeys. Importantly, MultiTEP platform enables development of vaccines targeting pathological molecules involved in various neurodegenerative disorders. Taking advantage of the universality of MultiTEP platform, we developed DNA vaccines targeting 3 B-cell epitopes (amino acids [aa]85-99, aa109-126, and aa126-140) of h ...[more]

PMID: 28870518

Similar Datasets

Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in 2019 and caused the coronavirus disease 2019 (COVID-19) pandemic worldwide. As of September 2023, the number of confirmed coronavirus cases has reached over 770 million and caused nearly 7 million deaths. The World Health Organization assigned and informed the characterization of variants of concern (VOCs) to help control the COVID-19 pandemic through global monitoring of circulating viruses. Although many vaccines have been proposed, developing an effective vaccine against variants is still essential to reach the endemic stage of COVID-19. We designed five DNA vaccine candidates composed of the first isolated genotype and major SARS-CoV-2 strains from isolated Korean patients classified as VOCs, such as Alpha, Beta, Gamma, and Delta. To evaluate the immunogenicity of each genotype via homologous and heterologous vaccination, mice were immunized twice within a 3-week interval, and the blood and spleen were collected 1 week after the final vaccination to analyze the immune responses. The group vaccinated with DNA vaccine candidates based on the S genotype and the Alpha and Beta variants elicited both humoral and cellular immune responses, with higher total IgG levels and neutralizing antibody responses than the other groups. In particular, the vaccine candidate based on the Alpha variant induced a highly diverse cytokine response. Additionally, we found that the group subjected to homologous vaccination with the S genotype and heterologous vaccination with S/Alpha induced high total IgG levels and a neutralization antibody response. Homologous vaccination with the S genotype and heterologous vaccination with S/Alpha and S/Beta significantly induced IFN-γ immune responses. The immunogenicity after homologous vaccination with S and Alpha and heterologous vaccination with the S/Alpha candidate was better than that of the other groups, indicating the potential for developing novel DNA vaccines against different SARS-CoV-2 variants.

Project description:Based on immunostainings and biochemical analyses, certain post-translationally modified alpha-synuclein (aSyn) variants, including C-terminally truncated (CTT) and Serine-129 phosphorylated (pSer129) aSyn, are proposed to be involved in the pathogenesis of synucleinopathies such as Parkinson's disease with (PDD) and without dementia (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). However, quantitative information about aSyn proteoforms in the human brain in physiological and different pathological conditions is still limited. To address this, we generated sequential biochemical extracts of the substantia nigra, putamen and hippocampus from 28 donors diagnosed and neuropathologically-confirmed with different synucleinopathies (PD/PDD/DLB/MSA), as well as Alzheimer's disease, progressive supranuclear palsy, and aged normal subjects. The tissue extracts were used to build a reverse phase array including 65 aSyn antibodies for detection. In this multiplex approach, we observed increased immunoreactivity in donors with synucleinopathies compared to controls in detergent-insoluble fractions, mainly for antibodies against CT aSyn and pSer129 aSyn. In addition, despite of the restricted sample size, clustering analysis suggested disease-specific immunoreactivity signatures in patient groups with different synucleinopathies. We aimed to validate and quantify these findings using newly developed immunoassays towards total, 119 and 122 CTT, and pSer129 aSyn. In line with previous studies, we found that synucleinopathies shared an enrichment of post-translationally modified aSyn in detergent-insoluble fractions compared to the other analyzed groups. Our measurements allowed for a quantitative separation of PDD/DLB patients from other synucleinopathies based on higher detergent-insoluble pSer129 aSyn concentrations in the hippocampus. In addition, we found that MSA stood out due to enrichment of CTT and pSer129 aSyn also in the detergent-soluble fraction of the SN and putamen. Together, our results achieved by multiplexed and quantitative immunoassay-based approaches in human brain extracts of a limited sample set point to disease-specific biochemical aSyn proteoform profiles in distinct neurodegenerative disorders.

Dataset Information

MultiTEP platform-based DNA vaccines for alpha-synucleinopathies: preclinical evaluation of immunogenicity and therapeutic potency.

Publications

MultiTEP platform-based DNA vaccines for alpha-synucleinopathies: preclinical evaluation of immunogenicity and therapeutic potency.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets