Document text
Principal Investigator: Jordan Green
Organization: JOHNS HOPKINS UNIVERSITY
Fiscal Year: 2021
Award: $204,688
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
Multiple sclerosis (MS) is the leading cause of non-traumatic disability in young adults in the United
States. In MS, the immune system attacks autoantigens in the myelin sheath of the central nervous system
(CNS), leading to neurological degeneration, and there is currently no cure. A treatment for MS that does not
cause general immunosuppression is urgently needed. One leading strategy for this is to induce antigen-specific
immune tolerance, which can prevent immune responses against the myelin sheath without having a systemic
suppressive effect. In order to accomplish this, we propose to use synthetic, biodegradable polymeric
nanoparticles to deliver mRNA encoding the MS autoantigen myelin oligodendrocyte glycoprotein
(MOG) to antigen-presenting cells (APCs) as a tolerogenic nanoparticle (NP)-based vaccine. By
engineering the NPs to selectively target the liver, where APCs express low levels of activating signals and
surrounding cells secrete high concentrations of immunosuppressive signals, we will enable presentation of the
MOG antigen to T cells in a tolerogenic context. As a second layer of safety to prevent inadvertent immune
stimulation targeting the MOG antigen, we will co-deliver an immunosuppressive agent. This is designed to lead
to expansion of MOG-specific regulatory T cells (Tregs), which will provide antigen-specific protective
immunosuppression. At the same time, in the absence of activating co-stimulatory molecules, the transfected
APCs can also cause anergy or death of MOG-specific Th1, Th17, and CD8+ T cells, thereby preventing such
cells from causing disease. This proposal will further optimize the NP formulations to maximize APC transfection,
minimize unintended immune activation, and further improve in vivo delivery of NPs selectively. This NP
technology represents an innovative vaccine platform for preventing or treating MS, with advantages of safety
and ease of manufacture compared to other related technologies, such as the use of viral vectors for gene
delivery.
Terms: <Antigen Presentation><Antigen-Presenting Cells><Antigens><Artificial nano particles><Artificial nanoparticles><Autoantigens><Autoimmune><Autoimmune Diseases><Autologous Antigens><Biocompatible Materials><Biomaterials><Blood monocyte><Body Tissues><Brain><Brain Nervous System><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CD8><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CD8B><CD8B1><CD8B1 gene><CNS Nervous System><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Central Nervous System><Cessation of life><Co-culture><Cocultivation><Coculture><Coculture Techniques><Death><Dendritic Cells><Disease><Disorder><Disseminated Sclerosis><EAE><Encephalon><Engineering><Ensure><Environment><Esters><Experimental Allergic Encephalitis><Experimental Allergic Encephalomyelitis><Experimental Autoimmune Encephalitis><Experimental Autoimmune Encephalomyelitis><Formulation><Gene Delivery><Genes><Genetic Engineering><Genetic Engineering Biotechnology><Genetic Engineering Molecular Biology><GpG-ODN><GpG-oligonucleotide><Health><Human><Immune><Immune Cell Activation><Immune Tolerance><Immune response><Immune system><Immunes><Immunization><Immunocompromised><Immunocompromised Host><Immunocompromised Patient><Immunologic Receptors><Immunologic Sensitization><Immunologic Stimulation><Immunologic Tolerance><Immunological Receptors><Immunological Sensitization><Immunological Stimulation><Immunological response><Immunomodulation><Immunostimulation><Immunosuppressants><Immunosuppressed Host><Immunosuppression><Immunosuppression Effect><Immunosuppressive Agents><Immunosuppressive Effect><Immunosuppressive drug><Immunosuppressive treatment><In Vitro><Incidence><Inflammation><Injections><Intracellular Communication and Signaling><Intravenous><LYT3><Lead><Liver><MOG glycoprotein><MS treatment><Marrow monocyte><Mediating><Messenger RNA><Methods><Mice><Mice Mammals><Modeling><Modern Man><Multiple Sclerosis><Murine><Mus><Muscle><Muscle Tissue><Myelin Sheath><Mφ><Nerve><Nerve Degeneration><Neuraxis><Neuron Degeneration><Nucleic Acids><Oligo><Oligonucleotides><Organ><Patients><Pb element><Prevention><Property><Recombinant DNA Technology><Regulatory T-Lymphocyte><Reporter Genes><Risk><Safety><Scheme><Self-Antigens><Severity of illness><Sight><Signal Transduction><Signal Transduction Systems><Signaling><Specificity><T-Cells><T-Lymphocyte><T4 Cells><T4 Lymphocytes><T8 Cells><T8 Lymphocytes><Technology><Time><Tissues><Toxic effect><Toxicities><Transfection><Transgenic Mice><Treg><United States><Vaccines><Veiled Cells><Viral Vector><Virus><Vision><Work><accessory cell><adult youth><allergic/immunologic body system><allergic/immunologic organ system><anergy><autoimmune condition><autoimmune disorder><autoimmune encephalomyelitis><autoreactivity><base><biodegradable polymer><biological material><biological signal transduction><biophysical characteristics><biophysical characterization><biophysical measurement><biophysical parameters><biophysical properties><bioresorbable polymer><cell type><chemical property><conventional therapy><conventional treatment><cytokine><degradable polymer><design><designing><disability><disease severity><engineered immune system><engineered nano particle><engineered nanoparticle><genetic vaccine><genetically engineered><heavy metal Pb><heavy metal lead><hepatic body system><hepatic organ system><host response><immune activation><immune engineering><immune modulation><immune receptor><immune regulation><immune suppression><immune suppressive agent><immune suppressor><immune system response><immune system tolerance><immune unresponsiveness><immunoengineering><immunogen><immunogenicity><immunologic reactivity control><immunological paralysis><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><immunosuppressed patient><immunosuppressive substance><immunosuppressor><improved><in vivo><innovate><innovation><innovative><insular sclerosis><intravenous administration><lymph organ><lymphatic organ><lymphoid organ><mRNA><mRNA delivery><macrophage><monocyte><motor impairment><mouse model><movement impairment><movement limitation><multiple sclerosis treatment><murine model><muscular><myelin oligodendrocyte glycoprotein><nano particle><nano particle delivery><nano-sized particle><nanoparticle><nanoparticle delivered><nanoparticle delivery><nanosized particle><neural degeneration><neurodegeneration><neurodegenerative><neurological degeneration><neuronal degeneration><next generation><non-viral gene delivery><nonviral gene delivery><oligodendrocyte-myelin glycoprotein><oligos><particle><prevent><preventing><recruit><regulatory T-cells><response><side effect><site targeted delivery><targeted delivery><thymus derived lymphocyte><vector><visual function><young adult><young adulthood>