Active Amyloid-β Vaccination Results in Epigenetic Changes in the Hippocampus of an Alzheimer's Disease-Like Mouse Model.
4区 · 医学
作者: Roy Lardenoije ; Daniël L A van den Hove ; Sophie E Jung ; Monique Havermans ; Peter Blackburn ; Bin Liu ; Bart P F Rutten ; Cynthia A Lemere
While evidence accumulates for a role of epigenetic modifications in the pathophysiological cascade of Alzheimer's disease (AD), amyloid-β (Aβ)-targeted active immunotherapy approaches are under investigation to prevent or slow the progression of AD. The impact of Aβ active vaccines on epigenetic markers has not been studied thus far.
The current study aims to establish the relationship between active immunotherapy with a MER5101-based vaccine (consisting of Aβ1-15 copies conjugated with a 7 aa spacer to the diphtheria toxoid carrier protein, formulated in a Th2-biased adjuvant) and epigenetic DNA modifications in the hippocampus of APPswe/PS1dE9 mice.
As we previously reported, immunotherapy started when the mice were 10 months of age and behavioral testing occurred at 14 months of age, after which the mice were sacrificed for further analysis of their brains. In this add-on study, global levels of DNA methylation and hydroxymethylation, and DNA methyltransferase 3A (DNMT3A) were determined using quantitative immunohistochemistry, and compared to our previously analyzed immunization-induced changes in AD-related neuropathology and cognition.
Active immunization did not affect global DNA methylation levels but instead, resulted in decreased DNA hydroxymethylation and DNMT3A levels. Independent of immunization, inverse correlations with behavioral performance were observed for levels of DNA methylation and hydroxymethylation, as well as DNMT3A, while Aβ pathology and synaptic markers did not correlate with DNA methylation levels but did positively correlate with DNA hydroxymethylation and levels of DNMT3A.
Our results indicate that active Aβ vaccination has significant effects on the epigenome in the hippocampus of APPswe/PS1dE9 mice, and suggest that DNA methylation and hydroxymethylation may be involved in cognitive functioning.
2016-06-01·Journal of Neurochemistry2区 · 医学
A retrospective analysis of the Alzheimer's disease vaccine progress - The critical need for new development strategies
2区 · 医学
作者: Marciani, Dante J.
The promising results obtained with aducanumab and solanezumab against Alzheimer's disease (AD) strengthen the vaccine approach to prevent AD, despite of the many clinical setbacks. It has been problematic to use conjugated peptides with Th1/Th2 adjuvants to induce immune responses against conformational epitopes formed by Aβ oligomers, which is critical to induce protective antibodies. Hence, vaccination should mimic natural immunity by using whole or if possible conjugated antigens, but biasing the response to Th2 with anti-inflammatory adjuvants. Also, selection of the carrier and cross-linking agents is important to prevent suppression of the immune response against the antigen. That certain compounds having phosphorylcholine or fucose induce a sole Th2 immunity would allow antigens with T-cell epitopes without inflammatory autoimmune reactions to be used. Another immunization method is DNA vaccines combined with antigenic ones, which favors the clonal selection and expansion of high affinity antibodies needed for immune protection, but this also requires Th2 immunity. Since AD transgenic mouse models have limited value for immunogen selection as shown by the clinical studies, screening may require the use of validated antibodies and biophysical methods to identify the antigens that would be most likely recognized by the human immune system and thus capable to stimulate a protective antibody response. To induce an anti-Alzheimer's disease protective immunity and prevent possible damage triggered by antigens having B-cell epitopes-only, whole antigens might be used; while inducing Th2 immunity with sole anti-inflammatory fucose-based adjuvants. This approach would avert a damaging systemic inflammatory immunity and the suppression of immunoresponse against the antigen because of carrier and cross-linkers; immune requirements that extend to DNA vaccines.
2013-04-17·Journal of Neuroscience1区 · 医学
MER5101, a novel Aβ1-15:DT conjugate vaccine, generates a robust anti-Aβ antibody response and attenuates Aβ pathology and cognitive deficits in APPswe/PS1ΔE9 transgenic mice
1区 · 医学
作者: Liu, Bin ; Frost, Jeffrey L. ; Sun, Jing ; Fu, Hongjun ; Grimes, Stephen ; Blackburn, Peter ; Lemere, Cynthia A.
Active amyloid-β (Aβ) immunotherapy is under investigation to prevent or treat early Alzheimer's disease (AD). In 2002, a Phase II clinical trial (AN1792) was halted due to meningoencephalitis in ∼6% of the AD patients, possibly caused by a T-cell-mediated immunological response. Thus, generating a vaccine that safely generates high anti-Aβ antibody levels in the elderly is required. In this study, MER5101, a novel conjugate of Aβ1-15 peptide (a B-cell epitope fragment) conjugated to an immunogenic carrier protein, diphtheria toxoid (DT), and formulated in a nanoparticular emulsion-based adjuvant, was administered to 10-month-old APPswe/PS1ΔE9 transgenic (Tg) and wild-type (Wt) mice. High anti-Aβ antibody levels were observed in both vaccinated APPswe/PS1ΔE9 Tg and Wt mice. Antibody isotypes were mainly IgG1 and IgG2b, suggesting a Th2-biased response. Restimulation of splenocytes with the Aβ1-15:DT conjugate resulted in a strong proliferative response, whereas proliferation was absent after restimulation with Aβ1-15 or Aβ1-40/42 peptides, indicating a cellular immune response against DT while avoiding an Aβ-specific T-cell response. Moreover, significant reductions in cerebral Aβ plaque burden, accompanied by attenuated microglial activation and increased synaptic density, were observed in MER5101-vaccinated APPswe/PS1ΔE9 Tg mice compared with Tg adjuvant controls. Last, MER5101-immunized APPswe/PS1ΔE9 Tg mice showed improvement of cognitive deficits in both contextual fear conditioning and the Morris water maze. Our novel, highly immunogenic Aβ conjugate vaccine, MER5101, shows promise for improving Aβ vaccine safety and efficacy and therefore, may be useful for preventing and/or treating early AD.
A phase I clinical trial to evaluate the safety and tolerability of a first-of-its-kind vaccine against Alzheimer's disease
NEWPORT BEACH, Calif., March 2, 2023 /PRNewswire/ -- Hoag's Pickup Family Neurosciences Institute has started enrolling participants for a Phase 1 clinical trial evaluating the safety and tolerability of a first-of-its-kind Alzheimer's disease vaccine. The hope is that the vaccine will eventually be used to prevent Alzheimer's disease in healthy people who are at risk.
Hoag is the only site in California among total six sites in the United States selected to participate in the study. This study is supported by a grant from the National Institute of Aging, a division of the National Institute of Health, to the study sponsor - the Institute of Molecular Medicine (Huntington Beach, CA) and its collaborators at the University of California, Irvine and the University of Southern California. This Phase 1 study is being conducted by Clinartis CRO, Miami, and includes eligible subjects aged 60 to 85 years with early symptoms of Alzheimer's disease. The goal of the study is to evaluate the safety and tolerability of the vaccine, and also to assess the vaccine's impact on the levels of beta-amyloid in the brain, one of the associated biomarkers of Alzheimer's disease, using positron emissions tomography (PET) scans
"Everything about this trial is groundbreaking," said Gus Alva, M.D., D.F.A.P.A, the principal investigator of the study at Hoag. "It's the first-in-human MultiTEP platform-based nucleic acid vaccine that, with successful trials, could be used to prevent the development of Alzheimer's disease in cognitively health people but at risk of developing the disease, rather than waiting for the disease to manifest clinically and then slowing the progression.
The beta-amyloid vaccine induces a cellular immune response through a unique process that was proven in animal studies to reduce the misfolded amyloid plaques found in the brains of people contending with Alzheimer's disease.
"The goal is to develop an immunogenic vaccine to prevent this dreaded disease that now afflicts one in eight people over the age of 65," said Michael Brant-Zawadzki, M.D., Hoag's Senior Physician Executive, and the Ron and Sandi Simon Executive Medical Director Endowed Chair of the Pickup Family Neurosciences Institute. He credits Hoag's reputation within the field for its selection for this trial – as well as Hoag's longstanding memory and cognitive program caring for patients with this disease, and previous participation in a host of other innovative Alzheimer's disease trials.
"The world-class talent we have here at Hoag attracts these very innovative projects," Dr. Brant-Zawadzki said. "We are able to offer our patients access to innovative care pathways, as well as access to these types of early-stage break-through trials. It's a tremendous honor and speaks to the caliber of research and expertise here at Hoag."
"After decades of effort, the medical field is able to offer Alzheimer's patients options. There is a whole menu of treatments becoming available, and now a possible prevention, that patients can choose from based on what might fit them best," Dr. Alva said. "We are very excited to be at the forefront of those opportunities, especially the vaccine. Most of the at-risk people in the U.S. don't get a crack at this vaccine, but the residents of Orange County do."
Hoag's Pickup Family Neurosciences Institute is currently offering many other Alzheimer's clinical trials. For more information or to enroll, call 949-764-6797 or email [email protected].
ABOUT HOAG'S PICKUP FAMILY NEUROSCIENCES INSTITUTE
Delivering a personalized, integrated approach using best-practice guidelines, the most advanced technology, and integration of medical specialists in the most appropriate facilities, the Pickup Family Neurosciences Institute (PFNI) at Hoag provides world class care for patients with specific conditions of the brain and spine such as stroke, aneurysms and vascular malformations, brain tumors, epilepsy, movement disorders, memory and cognitive disorders, pain, minimally invasive spine surgery, multiple sclerosis, addiction medicine and sleep disorders, as well as the mind-body interface of behavioral health. Many of Hoag's PFNI programs have received high acclaim. The Hoag Stroke Program was the first in Orange County and the second in California to be named a Certified Comprehensive Stroke Center by DNV GL Healthcare and was awarded the American Stroke Association's Get With The Guidelines Stroke Gold Plus Performance Achievement for stroke care. And as one of the first centers in the U.S. to offer the most advanced radiosurgical treatment system available, Leksell Gamma Knife® Perfexion™, the PFNI brain tumor program is the largest in Orange County and is also among the top volume programs in the western United States. Hoag has been recognized as a designated Level 4 Comprehensive Epilepsy Center by the National Association of Epilepsy Centers. The PFNI's memory and cognitive disorders program is nationally recognized.
Hoag is a nonprofit, regional health care delivery system in Orange County, California. Delivering world-class, comprehensive, personalized care, Hoag consists of 1,800 top physicians, 15 urgent care facilities, 10 health & wellness centers, and two award-winning hospitals. Hoag offers a comprehensive blend of health care services that includes six institutes providing specialized services in the following areas: cancer, digestive health, heart and vascular, neurosciences, women's health, and orthopedics through Hoag's affiliate, Hoag Orthopedic Institute, which consists of an orthopedic hospital and four ambulatory surgical centers. Hoag is the highest ranked hospital in Orange County by U.S. News & World Report and the only OC hospital ranked in the Top 10 in California, as well as a designated Magnet® hospital by the American Nurses Credentialing Center (ANCC). For more information, visit hoag.org.
The Institute for Molecular Medicine (IMM) is a non-profit organization created with the goal of understanding, preventing, and curing chronic human diseases, including neurodegenerative disorders. IMM works closely with its partner, Nuravax: a biotechnology company that licenses IMM's patented technology. Based in Orange County, California, IMM, along with Nuravax, is advancing MultiTEP: a universal vaccine platform technology that supports the development of multiple vaccine designs based on DNA, RNA, or recombinant proteins.
Research reported in this press release was supported by the National Institute on Aging (NIA) division of the U.S. National Institutes of Health (NIH) under grant number R01-AG074983. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.