Davtyan Hayk, Zagorski Karen, Petrushina Irina, Kazarian Konstantin, Goldberg Natalie R S, Petrosyan Janet, Blurton-Jones Mathew, Masliah Eliezer, Cribbs David H, Agadjanyan Michael G, Ghochikyan Anahit
Department of Molecular Immunology, Institute for Molecular Medicine, Huntington Beach, CA, USA; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA, USA.
Department of Molecular Immunology, Institute for Molecular Medicine, Huntington Beach, CA, USA.
Neurobiol Aging. 2017 Nov;59:156-170. doi: 10.1016/j.neurobiolaging.2017.08.006. Epub 2017 Aug 10.
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 (hα-Syn) separately or all 3 epitopes simultaneously. All 4 DNA vaccines (1) generate high titers of anti-hα-Syn antibodies and (2) induce robust MultiTEP-specific T-helper cell responses without activation of potentially detrimental autoreactive anti-hα-Syn T-helper cells. Generated antibodies recognize misfolded hα-Syn produced by neuroblastoma cells, hα-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 hα-Syn simultaneously (PV-1950D) has been chosen for ongoing preclinical assessment in mouse models of hα-Syn with the aim to translate it to the human clinical trials.
我们之前已经证明，基于我们专有的MultiTEP平台技术的抗β淀粉样蛋白DNA疫苗（AV-1959D）在小鼠、兔子和猴子中具有极强的免疫原性。重要的是，MultiTEP平台能够开发针对各种神经退行性疾病中涉及的病理分子的疫苗。利用MultiTEP平台的通用性，我们分别或同时开发了针对人类α-突触核蛋白（hα-Syn）的3个B细胞表位（氨基酸[aa]85-99、aa109-126和aa126-140）的DNA疫苗。所有4种DNA疫苗（1）产生高滴度的抗hα-Syn抗体，（2）诱导强烈的MultiTEP特异性辅助性T细胞反应，而不会激活潜在有害的自身反应性抗hα-Syn辅助性T细胞。产生的抗体能够识别神经母细胞瘤细胞产生的错误折叠的hα-Syn、转基因小鼠品系脑组织中的hα-Syn以及路易体痴呆病例脑组织中的hα-Syn。基于这些结果，已选择最有前景的同时靶向hα-Syn的3个B细胞表位的疫苗（PV-1950D）在hα-Syn小鼠模型中进行正在进行的临床前评估，旨在将其转化为人体临床试验。
