The overall goal of this project is to develop a novel therapeutic for the treatment of demyelinatingdisease involving autoreactive antibodies specific for myelin oligodendrocyte glycoprotein (MOG).MOG antibody-associated disease (MOGAD) encompasses aquaporin-4-antibody seronegativeneuromyelitis optica spectrum disorder (NMOSD), acute disseminated encephalomyelitis, opticneuritis, myelitis and brainstem encephalomyelitis and usually affects children or young adults.The disease course is frequently relapsing, and can lead to blindness, debilitating paralysis andcognitive effects. Current treatment regimens for MOGAD suffer from serious limitations. Immunosuppressantssuch as prednisone/prednisolone or azathioprine lead to general immunosuppression and othersevere side effects. Plasma exchange to remove the autoreactive antibodies and otherinflammatory mediators results in adverse consequences in a high percentage of patients.Further, the delivery of B cell depleting antibodies such as rituximab has led to disappointingresults, with relapses in around 30% patients. Consequently, there is a pressing need to developnew and improved therapies for the potentially devastating effects of MOGAD. The development of therapeutics to selectively target the pathogenic antibodies is expectedto overcome the current problems associated with treating MOGAD. This application seeks toaddress this by generating engineered, antibody-based reagents that specifically and rapidlydeplete MOG-specific antibodies, whilst not affecting the levels of antibodies that have aprotective role against infection etc. This novel technology is called Seldeg technology (forselective degradation). The Specific aims of the study are: 1. To design and express Seldegs to target human MOG-specific antibodies. 2. To analyze the stability and binding activity of the Seldegs. This approach could not only be transformative for the management of the potentiallydevastating consequences of MOGAD, but would also lay the foundations for analogousapproaches to be taken in many other clinical settings where pathogenic antibodies lead todisease. PROJECT NARRATIVE
Treatments that are currently available for antibody-mediated autoimmune diseases such as
MOG antibody-associated disease (MOGAD) are generally immunosuppressive, are associated
with adverse events and/or have limited efficacy. To address this issue, in this application we
propose to develop a novel treatment that selectively removes the autoreactive antibodies which
are involved in the disease process, without affecting the levels of other antibodies that are
important for protection against infectious agents such as bacteria and viruses. This approach
has the potential to be a game-changer for the clinical management of MOGAD, in addition to
having broader relevance for the treatment of other antibody-mediated autoimmune diseases. Adult ; 21+ years old ; Adult Human ; adulthood ; Affect ; Antibodies ; Antibody Formation ; Ab response ; Antibody Production ; antibody biosynthesis ; immunoglobulin biosynthesis ; Antigens ; immunogen ; Autoantibodies ; autoimmune antibody ; autoreactive antibody ; self reactive antibody ; Autoimmune Diseases ; autoimmune condition ; autoimmune disorder ; Azathioprine ; Azothioprine ; Immuran ; Imuran ; Imurel ; B-Lymphocytes ; B blood cells ; B cell ; B cells ; B-Cells ; B-cell ; Bacteria ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Brain Stem ; Brainstem ; Child ; 0-11 years old ; Child Youth ; Children (0-21) ; youngster ; Clinical Trials ; Demyelinating Diseases ; Demyelinating Disorders ; Disadvantaged ; Disease ; Disorder ; Acute Disseminated Encephalomyelitis ; acute disseminated encephalitis ; Encephalomyelitis ; Myeloencephalitis ; Engineering ; Foundations ; Goals ; Human ; Modern Man ; Immune Tolerance ; Immunologic Tolerance ; immune system tolerance ; immune unresponsiveness ; immunological paralysis ; Immunosuppression ; Immunosuppression Effect ; Immunosuppressive Effect ; immune suppression ; Immunosuppressive Agents ; Immunosuppressants ; Immunosuppressive drug ; Immunosuppressive treatment ; immune suppressive agent ; immune suppressor ; immunosuppressive substance ; immunosuppressor ; Infection ; Kupffer Cells ; Stellate Sinusoidal Macrophage ; liver macrophage ; Laboratories ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; Liver ; hepatic body system ; hepatic organ system ; Lysosomes ; Meningococcal Infections ; Myelitis ; Inflammatory Myelopathy ; Spinal Cord Inflammation ; Transverse Myelitis ; Transverse Myelopathy Syndrome ; Neuromyelitis Optica ; Devic Disease ; Devic's Syndrome ; Optic Neuritis ; Patients ; Plasma Exchange ; Play ; prednisolone ; 1,2-Dehydrohydrocortisone ; Delta(1)Hydrocortisone ; Delta-F ; Delta1-dehydro-hydrocortisone ; Deltahydrocortisone ; Metacortandralone ; Prednisolonum ; Prednisone ; 1, 2-Dehydrocortisone ; Dehydrocortisone ; Delta(1)-Cortisone ; Deltacortisone ; Deltadehydrocortisone ; Metacortandracin ; Prednisonum ; delta-Cortisone ; Reagent ; Cell Surface Receptors ; Relapse ; Research ; Research Design ; Study Type ; study design ; Risk ; Role ; social role ; Technology ; Texas ; Thrombosis ; thrombotic disease ; thrombotic disorder ; Translating ; Treatment Protocols ; Treatment Regimen ; Treatment Schedule ; Universities ; Virus ; Work ; oligodendrocyte-myelin glycoprotein ; MOG glycoprotein ; myelin oligodendrocyte glycoprotein ; Generations ; Intravenous Immunoglobulins ; IGIV ; IV Immunoglobulins ; IVIG ; Immune globulin IV ; Intravenous Antibodies ; Intravenous IG ; Intravenous Immune Globulin ; Mediating ; Chimeric Proteins ; Chimera Protein ; Fusion Protein ; base ; improved ; Procedures ; Clinical ; Encapsulated ; Phase ; Variant ; Variation ; Endothelial Cells ; Plasmablast ; Serum ; Blood Serum ; Childhood ; pediatric ; Recovery ; young adult ; adult youth ; young adulthood ; Inflammation Mediators ; inflammatory mediator ; Funding ; Antibody Therapy ; antibody based therapies ; antibody treatment ; antibody-based therapeutics ; antibody-based treatment ; AQP4 protein ; aquaporin 4 ; Therapeutic ; infectious organism ; Infectious Agent ; Inflammatory ; Cognitive Disturbance ; Cognitive Impairment ; Cognitive decline ; Cognitive function abnormal ; Disturbance in cognition ; cognitive dysfunction ; cognitive loss ; Impaired cognition ; Intravenous ; C2B8 Monoclonal Antibody ; MabThera ; Rituxan ; rituximab ; Frequencies ; Clinic ; vision loss ; visual loss ; Blindness ; Palsy ; Plegia ; paralysis ; paralytic ; Paralysed ; novel ; novel technologies ; new technology ; Pathogenesis ; Abscission ; Extirpation ; Removal ; Surgical Removal ; resection ; Excision ; Sampling ; Property ; Adverse Experience ; Adverse event ; unpublished works ; Central Vein ; Pathogenicity ; Molecular Interaction ; Binding ; ward ; Bp35 ; CD20 ; Leu-16 ; MS4A1 ; MS4A2 ; MS4A1 gene ; Address ; Dose ; Data ; Grant Proposals ; Applications Grants ; in vivo ; Clinical Management ; Cognitive ; Pathologic ; Process ; design ; designing ; novel strategies ; new approaches ; novel approaches ; novel strategy ; Outcome ; targeted delivery ; site targeted delivery ; Population ; novel therapeutics ; new drug treatments ; new drugs ; new therapeutics ; new therapy ; next generation therapeutics ; novel drug treatments ; novel drugs ; novel therapy ; mouse model ; murine model ; therapeutic development ; therapeutic agent development ; comparative efficacy ; compare efficacy ; adverse outcome ; adverse consequence ; side effect ; infection risk ;
