The long-term goal of this project is to develop a treatment for the autoimmune disease multiple sclerosis (MS) that will suppress the immune system in an antigen-specific manner, has a low potential for serious side effects, and is easy to administer. Current treatments for multiple sclerosis (MS), most of which broadly suppress the immune system, are only partially effective and encumbered by side effects or the necessity for frequent injections that leads to a high degree of non-compliance. Using experimental autoimmune encephalomyelitis (EAE), the putative animal model of MS, Anergix developed an antigen-specific gene therapy treatment, in which fibroblasts, transduced to secrete an encephalogenic peptide, when injected into sick mice, cause a dramatic reduction in relapse rate and a profound decrease in the number of lymphocytes in the brain, as well as an alteration in the cytokine profiles to an anti-inflammatory phenotype. Sequestering the transduced cells within an implantable chamber that allowed diffusion of the peptide epitope enabled the use of an allogeneic cell line for therapy. As Anergix moves this therapy towards the clinic, the specific aims of this SBIR Phase I project are: * to identify overt immune alterations, particularly evidence of an anti-inflammatory response, that can be attributed to our therapy and that can be used in a clinical trial to monitor for safety, * to generate and characterize the MBP peptide-secreting human fibroblasts (MRC5-MBP) that will constitute Anergix's therapy Immune studies will be conducted in the SJL/J EAE model and will investigate myelin antigen-specific proliferation and peptide recall cytokine responses. In vivo bioluminescent imaging of MRC5 cells transduced with the luciferase gene will be used to characterize the proliferation, lifespan and survivability of encapsulated transduced cells and mass spectrometry will be used to measure secreted peptide. At the conclusion of these studies, we will have identified immune parameters that are influenced by our cell-based therapy for the treatment of multiple sclerosis, and also characterized the therapeutic cell line we plan to use in a phase 1 clinical trial (milestone). At this point, we will submit an SBIR Phase II application addressing production of a therapeutic Master Cell Bank, and animal toxicology and tumorgenicity studies using this cell bank. These studies were requested by the FDA during the Anergix pre-IND meeting in November 2007.
Public Health Relevance: Currently available disease modifying therapies (DMTs) for MS have many drawbacks including frequent injections and side effects which have limited their market penetration and led to unusually high non-compliance rates.12,13 More than one-third of MS patients stop taking DMTs within 12-18 months. The low dose antigen specific therapy that Anergix is developing for the clinic promises to reduce side effects, reduce the burden of more frequent treatments, and thereby improve patient compliance, leading to better disease management over the lifetime of the patient.
Thesaurus Terms: Atgn; Address; Adverse Effects; Allogenic; Animal Model; Animal Models And Related Studies; Animals; Anti-Inflammatories; Anti-Inflammatory Agents; Anti-Inflammatory; Antigenic Determinants; Antigens; Antiinflammatories; Antiinflammatory Agents; Assay; Athymic Nude Mouse; Autoimmune Diseases; B Cell Activating Factor; B Cell Growth Factor; B-Cell Differentiation Factor-1; B-Cell Growth Factor-1; B-Cell Growth Factor-I; B-Cell Proliferating Factor; B-Cell Stimulating Factor; B-Cell Stimulating Factor-1; B-Cell Stimulation Factor-1; B-Cell Stimulatory Factor-1; Baf; Bcdf-1; Bcgf; Bcgf-1; Bcsf 1; Bsf-1; Bsf1; Bsf1 (B Cell Stimulating Factor 1); Benign; Binding Determinants; Binetrakin; Bioassay; Biologic Assays; Biological Assay; Brain; Csif; Csif-10; Cell Communication And Signaling; Cell Line; Cell Lines, Strains; Cell Signaling; Cell Therapy; Cellline; Cells; Central Nervous System; Characteristics; Cities; Clinic; Clinical Trials; Clinical Trials, Phase I; Clinical Trials, Unspecified; Collaborations; Compliance Behavior; Core Facility; Cytokine Synthesis Inhibitory Factor; Cytokine Formation-Inhibiting Factor (Mouse Clone F115 Protein Moiety Reduced); Devices; Diffusion; Diploid Cells; Disease; Disease Management; Disease Progression; Disorder; Disorder Management; Dose; Eae; Early-Stage Clinical Trials; Encapsulated; Encephalomyelitis; Encephalomyelitis, Allergic; Encephalon; Encephalons; Ensure; Epitopes; Experimental Allergic Encephalitis; Experimental Allergic Encephalomyelitis; Experimental Autoimmune Encephalitis; Experimental Autoimmune Encephalomyelitis; Fibroblasts; Gene Transfer Clinical; Gene Transfer Procedure; Gene-Tx; Generalized Growth; Genetic Intervention; Goals; Growth; Hour; Human; Human, General; Il-10; Il-4; Il10; Il10a; Il4; Il4 Protein; Itx; Ice; Image; Immune; Immune System; Immunologically Directed Therapy; Immunotherapy; Implant; Inflammatory Response; Injection Of Therapeutic Agent; Injections; Interleukin 10 Precursor; Interleukin-10; Interleukin-4; Interleukin-4 Precursor; Intervention, Genetic; Intracellular Communication And Signaling; Length Of Life; Lesion; Longevity; Luc Gene; Luciferase Gene; Lymphocyte Count; Lymphocyte Number; Lymphocyte Stimulatory Factor 1; Mcgf-2; Mr Imaging; Mr Tomography; Mri; Ms (Multiple Sclerosis); Magnetic Resonance Imaging; Magnetic Resonance Imaging Scan; Mammals, Mice; Man (Taxonomy); Man, Modern; Marketing; Mass Spectrum; Mass Spectrum Analysis; Mast Cell Growth Factor-2; Measures; Mediating; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; Methods And Techniques; Methods, Other; Mice; Mice, Athymic; Mice, Nude; Modeling; Molecular Biology, Gene Therapy; Monitor; Multiple Sclerosis; Murine; Mus; Myelin; Myelin Basic Proteins; Myeloencephalitis; Nmr Imaging; Nmr Tomography; Nervous System, Brain; Nervous System, Cns; Neuraxis; Nuclear Magnetic Resonance Imaging; Nude Mice; Patient Compliance; Patient Cooperation; Patients; Penetration; Peptides; Phase; Phase 1 Clinical Trials; Phase I Clinical Trials; Phase I Study; Phenotype; Photometry/Spectrum Analysis, Mass; Production; Protocol; Protocols Documentation; Recommendation; Relapse; Retroviral Vector; Retrovirus Vector; Sbir; Sbirs (R43/44); Safety; Sclerosis, Disseminated; Signal Transduction; Signal Transduction Systems; Signaling; Small Business Innovation Research; Small Business Innovation Research Grant; Spectrometry, Mass; Spectroscopy, Mass; Spectrum Analyses, Mass; Spectrum Analysis, Mass; T-Cell Growth Factor 2; T-Cells; T-Lymphocyte; Techniques; Technology; Therapeutic; Therapy, Cell; Therapy, Dna; Thymus-Dependent Lymphocytes; Time; Tissue Growth; Total Lymphocyte Count; Toxicology; Treatment Compliance; Treatment Side Effects; Zeugmatography; Autoimmune Disorder; Autoimmune Encephalomyelitis; Biological Signal Transduction; Body System, Allergic/Immunologic; Cell Bank; Cell Transduction; Cell-Based Therapy; Cellular Transduction; Clinical Investigation; Compliance Cooperation; Cultured Cell Line; Cytokine; Disease/Disorder; Dosage; Experiment; Experimental Research; Experimental Study; Gene Therapy; Genetic Therapy; Imaging; Immune Therapy; Immunogen; Implantation; Improved; In Vivo; Insular Sclerosis; Life Span; Lifespan; Meetings; Model Organism; Next Generation; Non-Compliance; Novel; Ontogeny; Organ System, Allergic/Immunologic; Patient Adherence; Phase 1 Study; Phase 1 Trial; Phase I Trial; Preclinical Study; Protocol, Phase I; Public Health Relevance; Research Study; Response; Side Effect; Stable Isotope; Therapy Adverse Effect; Therapy Compliance; Therapy Cooperation; Thymus Derived Lymphocyte; Transduced Cells; Treatment Adverse Effect
