Multiple sclerosis (MS) is a chronic, immune-mediated demyelinating disease of the central nervous system. Animal models of MS have been critical for elucidating MS pathological mechanisms and how they may be targeted for therapeutic intervention. Here we review the most commonly used animal models of MS. Although these animal models cannot fully replicate the MS disease course, a number of models have been developed to recapitulate certain stages. Experimental autoimmune encephalomyelitis (EAE) has been used to explore neuroinflammatory mechanisms and toxin-induced demyelinating models to further our understanding of oligodendrocyte biology, demyelination and remyelination. Zebrafish models of MS are emerging as a useful research tool to validate potential therapeutic candidates due to their rapid development and amenability to genetic manipulation.

https://journals.sagepub.com/doi/pdf/10.1177/1352458518805246

Animal models of multiple sclerosis: From rodents to zebrafish.

Nonviral delivery of plasmid (p)DNA or messenger (m)RNA is a safe and promising therapeutic option to continuously supply therapeutic proteins into diseased tissues. In most cases of in vivo pDNA and mRNA delivery, these nucleic acids are loaded into carriers based on cationic polymers and/or lipids to prevent nuclease-mediated degradation before reaching target cells. The carriers should also evade host clearance mechanisms, including uptake by scavenger cells and filtration in the spleen. Installation of ligands onto the carriers can facilitate their rapid uptake into target cells. Meanwhile, carrier toxicity should be minimized not only for preventing undesirable adverse responses in patients, but also for preserving the function of transfected cells to exert therapeutic effects. Long-term progressive improvement of platform technologies has helped overcome most of these issues, though some still remain hindering the widespread clinical application of nonviral pDNA and mRNA delivery. This review discusses design concepts of nonviral carriers for in vivo delivery and the issues to be overcome, focusing especially on our own efforts using polyplex micelles. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 978-990, 2019.

Design concepts of polyplex micelles for in vivo therapeutic delivery of plasmid DNA and messenger RNA.

Multiple sclerosis (MS) is an inflammatory, demyelinating and neurodegenerative disease of the central nervous system with unknown etiology. Currently approved disease-modifying treatment modalities are immunomodulatory or immunosuppressive. While the applied drugs reduce the frequency and severity of the attacks, their efficacy to regenerate myelin membranes and to halt disease progression is limited. To achieve such therapeutic aims, understanding biological mechanisms of remyelination and identifying factors that interfere with remyelination in MS can give respective directions. Such a perspective is given by the emerging functional profile of galectins. They form a family of tissue lectins, which are potent effectors in processes as diverse as adhesion, apoptosis, immune mediator release or migration. This review focuses on endogenous and exogenous roles of galectins in glial cells such as oligodendrocytes, astrocytes and microglia in the context of de- and (re)myelination and its dysregulation in MS. Evidence is arising for a cooperation among family members so that timed expression and/or secretion of galectins-1, -3 and -4 result in modifying developmental myelination, (neuro)inflammatory processes, de- and remyelination. Dissecting the mechanisms that underlie the distinct activities of galectins and identifying galectins as target or tool to modulate remyelination have the potential to contribute to the development of novel therapeutic strategies for MS.

/pdf/the-emerging-role-of-galectins-in-re-myelination-and-its-e8yop2d509.pdf

The emerging role of galectins in (re)myelination and its potential for developing new approaches to treat multiple sclerosis

Multiple sclerosis (MS) is a progressive disease of the central nervous system (CNS) that involves damage to the myelin sheath surrounding axons. MS therapy is based on immunomodulatory drugs that reduce disease recurrence and severity. Vitamin D is a hormone whose immunomodulatory ability has been widely demonstrated, including in experimental autoimmune encephalomyelitis (EAE), which is an animal model of CNS inflammation. In this study, we evaluated the potential of very early intervention with the active form of vitamin D (1,25-dihydroxyvitamin D3) to control neuroinflammation during EAE development. EAE was induced in C57BL/6J mice and 1,25-dihydroxyvitamin D3 administration began 1 day after disease induction. This procedure decreased prevalence, clinical score, inflammation, and demyelination. It also reduced MHCII expression in macrophages and microglia as well as the level of oxidative stress and messenger RNA (mRNA) expression for NLRP3, caspase-1, interleukin (IL)-1β, CX3CR1, CCL17, RORc and Tbx21 at the CNS. Otherwise, mRNA expression for ZO-1 increased at the lumbar spinal cord. These effects were accompanied by the stabilization of blood-spinal cord barrier permeability. The results of this study indicate that early intervention with 1,25-dihydroxyvitamin D3 can control the neuroinflammatory process that is the hallmark of EAE and MS immunopathogenesis and should thus be explored as an adjunct therapy for MS patients.

Calcitriol Prevents Neuroinflammation and Reduces Blood-Brain Barrier Disruption and Local Macrophage/Microglia Activation.

Inhibitory receptor agonists: the future of autoimmune disease therapeutics?

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Repeated injections of the interferon-β (IFN-β) protein are required for relapse prevention therapy in patients with MS. IFN-β gene transfer can be an alternative treatment that continuously supplies IFN-β protein to the patient without requiring repeated injections. In a previous study, we constructed a novel long-term IFN-β-expressing plasmid vector (pMx-IFN-β). In the present study, we examined whether gene transfer of pMx-IFN-β could be effective for the treatment of MS in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Seven days after injection of the EAE-inducing peptide, the EAE mice received hydrodynamic injections pMx-IFN-β. The severity of EAE symptoms in the pMx-IFN-β-treated mice was significantly lower for 1 month than that observed in the untreated mice. An evaluation of blood–brain barrier (BBB) function, using Evans Blue, showed that injection of pMx-IFN-β suppressed the B...

Amelioration of Experimental Autoimmune Encephalomyelitis in Mice by Interferon-Beta Gene Therapy, Using a Long-Term Expression Plasmid Vector.

Safe and effective interferon-beta gene therapy for the treatment of multiple sclerosis by regulating biological activity through the design of interferon-beta-galectin-9 fusion proteins

Akane Tanioka

Papers

Amelioration of Experimental Autoimmune Encephalomyelitis in Mice by Interferon-Beta Gene Therapy, Using a Long-Term Expression Plasmid Vector.

Safe and effective interferon-beta gene therapy for the treatment of multiple sclerosis by regulating biological activity through the design of interferon-beta-galectin-9 fusion proteins