An animal model of anti-AQP4 autoimmunity
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Principal Investigator: Unsong Oh Organization: VIRGINIA COMMONWEALTH UNIVERSITY Fiscal Year: 2024 Award: $232,875 Funding agency: National Institute of Allergy and Infectious Diseases A pathogenic immune response targeting aquaporin-4 (AQP4) causes neuromyelitis optica spectrum disorder (AQP4 NMOSD), a disabling neurological illness that leads to blindness and paralysis. Recent advances in treatment for AQP4 NMOSD have improved its prognosis but are associated with increased risk of serious infections. As an autoimmune neurological illness with a well-defined autoantigen, AQP4 NMOSD should be amenable to a cure by antigen-specific ablation or tolerization. However, preclinical testing of antigen-specific tolerizing therapy for AQP4 NMOSD remains hampered by the lack of an animal model that recapitulates the autoimmunity and the pathology in the same animal. Current animal models of AQP4 NMOSD require adoptive transfer which introduces confounding variables that are difficult to resolve. The objective of this proposal is to develop a model that recapitulates the autoimmunity and the pathology of AQP4 NMOSD in the same animal and thereby develop an animal model suitable for preclinical testing of antigen-specific tolerization therapies. Aim 1.1 will establish anti-AQP4 autoimmunity in the AQP4 null (AQP4.lacZ) mouse. Aim 1.2 will test two methods to restore AQP4 expression in the AQP4.lacZ mouse: 1) AAV-mediated AQP4 transduction and 2) inducible (tamoxifen) and conditional (GFAP promoter) Cre recombinase system to restore AQP4 expression in the AQP4.lacZ mouse. Aim 1.3 will test the hypothesis that restoring AQP4 expression following immunization against AQP4 in the AQP4 null mouse will result in AQP4-directed autoimmunity and pathology in the same animal. The successful completion of the proposed research is expected to deliver a new animal model that more fully recapitulates the autoimmunity and the pathology of AQP4 NMOSD, and thereby overcome the shortcomings of the current models. Once this model is developed, it will make a positive impact by facilitating preclinical studies aimed at developing antigen-specific ablation/tolerization therapies as cure for AQP4 NMOSD. Terms: <7S Gamma Globulin><AAV vector><AAV-based vector><AQP4 protein><Ablation><Address><Adeno-Associated Viruses><Adoptive Transfer><Animal Model><Animal Models and Related Studies><Animals><Antigen Targeting><Antigens><Astroprotein><Autoantigens><Autoimmune><Autoimmune Status><Autoimmunity><Autologous Antigens><Blindness><CRE Recombinase><Confounding Factors (Epidemiology)><Confounding Variables><Dependoparvovirus><Dependovirus><Development><Devic Disease><Devic's Syndrome><Disabling><Disease><Disorder><Dose><Dysfunction><Enterobacteria phage P1 Cre recombinase><Epidemiologic Confounding Factor><Functional disorder><GFA-Protein><GFAP><Glial Fibrillary Acid Protein><Glial Fibrillary Acidic Protein><Glial Intermediate Filament Protein><IgG><Immune Tolerance><Immune response><Immunization><Immunoglobulin G><Immunologic Tolerance><Immunological response><Infection><KO mice><Knock-out Mice><Knockout Mice><Knowledge><LacZ><LacZ Genes><Mediating><Methods><Mice><Mice Mammals><Modeling><Murine><Mus><Neurologic><Neurological><Neuromyelitis Optica><Null Mouse><Palsy><Paralysed><Pathogenicity><Pathology><Physiopathology><Plegia><Preclinical Testing><Predisposition><Prognosis><R-Series Research Projects><R01 Mechanism><R01 Program><Research><Research Grants><Research Project Grants><Research Projects><Risk><Scheme><Self-Antigens><Susceptibility><System><Tamoxifen><Testing><Wild Type Mouse><adeno associated virus group><adeno-associated viral vector><adeno-associated virus vector><animal model development><antigen based test><antigen test><aquaporin 4><bacteriophage P1 recombinase Cre><barrier to testing><developmental><host response><hurdle to testing><immune system response><immune system tolerance><immune unresponsiveness><immunogen><immunological paralysis><immunoresponse><improved><innovate><innovation><innovative><model of animal><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><obstacle to testing><paralysis><paralytic><pathophysiology><pre-clinical study><pre-clinical testing><preclinical study><prevent relapse><promoter><promotor><relapse prevention><seropositive><testing barrier><testing hurdle><testing obstacle><tool><vision loss><visual loss><wildtype mouse>