Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Science 25 February 2000:
Vol. 287. no. 5457, pp. 1453 - 1460
DOI: 10.1126/science.287.5457.1453
Prev | Table of Contents | Next

Research Articles

An Oral Vaccine Against NMDAR1 with Efficacy in Experimental Stroke and Epilepsy

Matthew J. During, 13* Charles W. Symes, 1 Patricia A. Lawlor, 1 John Lin, 2 Jane Dunning, 1 Helen L. Fitzsimons, 1 David Poulsen, 3 Paola Leone, 3 Ruian Xu, 1 Bridget L. Dicker, 1 Janusz Lipski, 2 Deborah Young 1

The brain is generally considered immunoprivileged, although increasing examples of immunological responses to brain antigens, neuronal expression of major histocompatibility class I genes, and neurological autoimmunity have been recognized. An adeno-associated virus (AAV) vaccine generated autoantibodies that targeted a specific brain protein, the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor. After peroral administration of the AAV vaccine, transgene expression persisted for at least 5 months and was associated with a robust humoral response in the absence of a significant cell-mediated response. This single-dose vaccine was associated with strong anti-epileptic and neuroprotective activity in rats for both a kainate-induced seizure model and also a middle cerebral artery occlusion stroke model at 1 to 5 months following vaccination. Thus, a vaccination strategy targeting brain proteins is feasible and may have therapeutic potential for neurological disorders.

1 Department of Molecular Medicine and
2 Department of Physiology, University of Auckland School of Medicine, Auckland, New Zealand.
3 Department of Neurosurgery, Jefferson Medical College and Thomas Jefferson University, Philadelphia, PA 19107, USA.
*   To whom correspondence should be addressed. E-mail: matthew.during{at}mail.tju.edu

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Transient cytochalasin-D treatment induces apically administered rAAV2 across tight junctions for transduction of enterocytes.
Y.-Y. Fu, E. Sibley, and S.-C. Tang (2008)
J. Gen. Virol. 89, 3004-3008
   Abstract »    Full Text »    PDF »
Diagnostic and Pathogenic Significance of Glutamate Receptor Autoantibodies.
D. Pleasure (2008)
Arch Neurol 65, 589-592
   Abstract »    Full Text »    PDF »
Complement Is an Essential Component of the Immune Response to Adeno-Associated Virus Vectors.
A. K. Zaiss, M. J. Cotter, L. R. White, S. A. Clark, N. C. W. Wong, V. M. Holers, J. S. Bartlett, and D. A. Muruve (2008)
J. Virol. 82, 2727-2740
   Abstract »    Full Text »    PDF »
Vaccines Based on Novel Adeno-Associated Virus Vectors Elicit Aberrant CD8+ T-Cell Responses in Mice.
J. Lin, Y. Zhi, L. Mays, and J. M. Wilson (2007)
J. Virol. 81, 11840-11849
   Abstract »    Full Text »    PDF »
Anti-NR1 N-terminal-domain vaccination unmasks the crucial action of tPA on NMDA-receptor-mediated toxicity and spatial memory.
K. Benchenane, H. Castel, M. Boulouard, R. Bluthe, M. Fernandez-Monreal, B. D. Roussel, J. P. Lopez-Atalaya, S. Butt-Gueulle, V. Agin, E. Maubert, et al. (2007)
J. Cell Sci. 120, 578-585
   Abstract »    Full Text »    PDF »
Therapeutic Expression of an Anti-Death Receptor 5 Single-Chain Fixed-Variable Region Prevents Tumor Growth in Mice.
J. Shi, Y. Liu, Y. Zheng, Y. Guo, J. Zhang, P.-t. Cheung, R. Xu, and D. Zheng (2006)
Cancer Res. 66, 11946-11953
   Abstract »    Full Text »    PDF »
Gene therapy as a therapeutic approach for the treatment of rheumatoid arthritis: innovative vectors and therapeutic genes.
J. Adriaansen, M. J. B. M. Vervoordeldonk, and P. P. Tak (2006)
Rheumatology 45, 656-668
   Abstract »    Full Text »    PDF »
Novel Adeno-Associated Virus Vector Vaccine Restricts Replication of Simian Immunodeficiency Virus in Macaques.
P. R. Johnson, B. C. Schnepp, M. J. Connell, D. Rohne, S. Robinson, G. R. Krivulka, C. I. Lord, R. Zinn, D. C. Montefiori, N. L. Letvin, et al. (2005)
J. Virol. 79, 955-965
   Abstract »    Full Text »    PDF »
Stiff-person syndromes: Motor cortex hyperexcitability correlates with anti-GAD autoimmunity.
C. Koerner, B. Wieland, W. Richter, and H.-M. Meinck (2004)
Neurology 62, 1357-1362
   Abstract »    Full Text »    PDF »
A Nonproliferating Parvovirus Vaccine Vector Elicits Sustained, Protective Humoral Immunity following a Single Intravenous or Intranasal Inoculation.
G. A. Palmer, J. L. Brogdon, S. L. Constant, and P. Tattersall (2004)
J. Virol. 78, 1101-1108
   Abstract »    Full Text »    PDF »
MICA/NKG2D-Mediated Immunogene Therapy of Experimental Gliomas.
M. A. Friese, M. Platten, S. Z. Lutz, U. Naumann, S. Aulwurm, F. Bischof, H.-J. Buhring, J. Dichgans, H.-G. Rammensee, A. Steinle, et al. (2003)
Cancer Res. 63, 8996-9006
   Abstract »    Full Text »    PDF »
Immunotherapeutic Approaches to Alzheimer's Disease.
A. Monsonego and H. L. Weiner (2003)
Science 302, 834-838
   Abstract »    Full Text »    PDF »
Blood Test Detecting Autoantibodies to N-Methyl-D-aspartate Neuroreceptors for Evaluation of Patients with Transient Ischemic Attack and Stroke.
S. A. Dambinova, G. A. Khounteev, G. A. Izykenova, I. G. Zavolokov, A. Y. Ilyukhina, and A. A. Skoromets (2003)
Clin. Chem. 49, 1752-1762
   Abstract »    Full Text »    PDF »
Drug-mediated neuroprotection and antiepileptogenesis: Animal data.
A. Pitkanen (2002)
Neurology 59, S27-33
   Abstract »    Full Text »
A Novel N-Methyl-D-aspartate Receptor Open Channel Blocker with in Vivo Neuroprotectant Activity.
R. Planells-Cases, C. Montoliu, M. Humet, A. M. Fernandez, C. Garcia-Martinez, E. Valera, J. M. Merino, E. Perez-Paya, A. Messeguer, V. Felipo, et al. (2002)
J. Pharmacol. Exp. Ther. 302, 163-173
   Abstract »    Full Text »    PDF »
Prevention of in Vivo Excitotoxicity by a Family of Trialkylglycines, a Novel Class of Neuroprotectants.
C. Montoliu, M. Humet, J.-J. Canales, J. Burda, R. Planells-Cases, F. Sanchez-Baeza, T. Carbonell, E. Perez-Paya, A. Messeguer, A. Ferrer-Montiel, et al. (2002)
J. Pharmacol. Exp. Ther. 301, 29-36
   Abstract »    Full Text »    PDF »
Book Review: Recruiting the Immune Response to Promote Axon Regeneration in the Injured Spinal Cord.
S. David and S. S. Ousman (2002)
Neuroscientist 8, 33-41
   Abstract »    PDF »
Potential Cancer Therapy With the Fragile Histidine Triad Gene: Review of the Preclinical Studies.
H. Ishii, K. R. Dumon, A. Vecchione, L. Y. Y. Fong, R. Baffa, K. Huebner, and C. M. Croce (2001)
JAMA 286, 2441-2449
   Abstract »    Full Text »    PDF »
Future directions for epilepsy research.
M. P. Jacobs, G. D. Fischbach, M. R. Davis, M. A. Dichter, R. Dingledine, D. H. Lowenstein, M. J. Morrell, J. L. Noebels, M. A. Rogawski, S. S. Spencer, et al. (2001)
Neurology 57, 1536-1542
   Abstract »    Full Text »    PDF »
cAMP-Dependent Protein Kinase Mediates Activity-Regulated Synaptic Targeting of NMDA Receptors.
F. T. Crump, K. S. Dillman, and A. M. Craig (2001)
J. Neurosci. 21, 5079-5088
   Abstract »    Full Text »    PDF »
Fragile Histidine Triad Expression Delays Tumor Development and Induces Apoptosis in Human Pancreatic Cancer.
K. R. Dumon, H. Ishii, A. Vecchione, F. Trapasso, G. Baldassarre, F. Chakrani, T. Druck, E. F. Rosato, N. N. Williams, R. Baffa, et al. (2001)
Cancer Res. 61, 4827-4836
   Abstract »    Full Text »    PDF »
Hippocampal Synaptic Plasticity Involves Competition between Ca2+/Calmodulin-Dependent Protein Kinase II and Postsynaptic Density 95 for Binding to the NR2A Subunit of the NMDA Receptor.
F. Gardoni, L. H. Schrama, A. Kamal, W. H. Gispen, F. Cattabeni, and M. Di Luca (2001)
J. Neurosci. 21, 1501-1509
   Abstract »    Full Text »    PDF »
Adeno-associated viral vector-mediated gene transfer results in long-term enzymatic and functional correction in multiple organs of Fabry mice.
S.-C. Jung, I. P. Han, A. Limaye, R. Xu, M. P. Gelderman, P. Zerfas, K. Tirumalai, G. J. Murray, M. J. During, R. O. Brady, et al. (2001)
PNAS 98, 2676-2681
   Abstract »    Full Text »    PDF »
FHIT gene therapy prevents tumor development in Fhit-deficient mice.
K. R. Dumon, H. Ishii, L. Y. Y. Fong, N. Zanesi, V. Fidanza, R. Mancini, A. Vecchione, R. Baffa, F. Trapasso, M. J. During, et al. (2001)
PNAS
   Abstract »    Full Text »
Successful Interference with Cellular Immune Responses to Immunogenic Proteins Encoded by Recombinant Viral Vectors.
A. Sarukhan, S. Camugli, B. Gjata, H. von Boehmer, O. Danos, and K. Jooss (2001)
J. Virol. 75, 269-277
   Abstract »    Full Text »
Disease Mechanisms in Neuroscience.
(2000)
Neuroscientist 6, 223-224
   PDF »
Vaccine Against Stroke and Epilepsy Works in Rats.
(2000)
Journal Watch Psychiatry 2000, 19
   Full Text »
Vaccine Against Stroke and Epilepsy Works in Rats.
(2000)
Journal Watch (General) 2000, 3
   Full Text »
Protein Kinase C Activation Modulates alpha -Calmodulin Kinase II Binding to NR2A Subunit of N-Methyl-D-Aspartate Receptor Complex.
F. Gardoni, C. Bellone, F. Cattabeni, and M. Di Luca (2001)
J. Biol. Chem. 276, 7609-7613
   Abstract »    Full Text »    PDF »
Expression and Function of Lysophosphatidic Acid Receptors in Cultured Rodent Microglial Cells.
T. Moller, J. J. Contos, D. B. Musante, J. Chun, and B. R. Ransom (2001)
J. Biol. Chem. 276, 25946-25952
   Abstract »    Full Text »    PDF »
FHIT gene therapy prevents tumor development in Fhit-deficient mice.
K. R. Dumon, H. Ishii, L. Y. Y. Fong, N. Zanesi, V. Fidanza, R. Mancini, A. Vecchione, R. Baffa, F. Trapasso, M. J. During, et al. (2001)
PNAS 98, 3346-3351
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)