Remyelination Induced by a DNA Aptamer in a Mouse Model of Multiple Sclerosis

Multiple sclerosis (MS) is a debilitating inflammatory disease of the central nervous system (CNS) characterized by local destruction of the insulating myelin surrounding neuronal axons. With more than 200 million MS patients worldwide, the absence of treatments that prevent progression or induce repair poses a major challenge. Anti-inflammatory therapies have met with limited success only in preventing relapses. Previous screening of human serum samples revealed natural IgM antibodies that bind oligodendrocytes and promote both cell signaling and remyelination of CNS lesions in an MS model involving chronic infection of susceptible mice by Theiler’s encephalomyelitis virus and in the lysolecithin model of focal demyelination. This intriguing result raises the possibility that molecules with binding specificity for oligodendrocytes or myelin components may promote therapeutic remyelination in MS. Because of the size and complexity of IgM antibodies, it is of interest to identify smaller myelin-specific molecules with the ability to promote remyelination in vivo. Here we show that a 40-nucleotide single-stranded DNA aptamer selected for affinity to murine myelin shows this property. This aptamer binds multiple myelin components in vitro. Peritoneal injection of this aptamer results in distribution to CNS tissues and promotes remyelination of CNS lesions in mice infected by Theiler’s virus. Interestingly, the selected DNA aptamer contains guanosine-rich sequences predicted to induce folding involving guanosine quartet structures. Relative to monoclonal antibodies, DNA aptamers are small, stable, and non-immunogenic, suggesting new possibilities for MS treatment

A Single Dose of Neuron-Binding Human Monoclonal Antibody Improves Spontaneous Activity in a Murine Model of Demyelination

Our laboratory demonstrated that a natural human serum antibody, sHIgM12, binds to neurons in vitro and promotes neurite outgrowth. We generated a recombinant form, rHIgM12, with identical properties. Intracerebral infection with Theiler's Murine Encephalomyelitis Virus (TMEV) of susceptible mouse strains results in chronic demyelinating disease with progressive axonal loss and neurologic dysfunction similar to progressive forms of multiple sclerosis. To study the effects of rHIgM12 on the motor function of TMEV-infected mice, we monitored spontaneous nocturnal activity over many weeks. Nocturnal behavior is a sensitive measure of rodent neurologic function because maximal activity changes are expected to occur during the normally active night time monitoring period. Mice were placed in activity boxes eight days prior to treatment to collect baseline spontaneous activity. After treatment, activity in each group was continuously recorded over 8 weeks. We chose a long 8-week monitoring period for two reasons: (1) we previously demonstrated that IgM induced remyelination is present by 5 weeks post treatment, and (2) TMEV-induced demyelinating disease in this strain progresses very slowly. Due to the long observation periods and large data sets, differences among treatment groups may be difficult to appreciate studying the original unfiltered recordings. To clearly delineate changes in the highly fluctuating original data we applied three different methods: (1) binning, (2) application of Gaussian low-pass filters (GF) and (3) polynomial fitting. Using each of the three methods we showed that compared to control IgM and saline, early treatment with rHIgM12 induced improvement in both horizontal and vertical motor function, whereas later treatment improved only horizontal activity. rHIgM12 did not alter activity of normal, uninfected mice. This study supports the hypothesis that treatment with a neuron-binding IgM not only protects neurons in vitro, but also influences functional motor improvement

Evidence for the Role of B Cells and Immunoglobulins in the Pathogenesis of Multiple Sclerosis

The pathogenesis of multiple sclerosis (MS) remains elusive. Recent reports advocate greater involvement of B cells and immunoglobulins in the initiation and propagation of MS lesions at different stages of their ontogeny. The key role of B cells and immunoglobulins in pathogenesis was initially identified by studies in which patients whose fulminant attacks of demyelination did not respond to steroids experienced remarkable functional improvement following plasma exchange. The positive response to Rituximab in Phase II clinical trials of relapsing-remitting MS confirms the role of B cells. The critical question is how B cells contribute to MS. In this paper, we discuss both the deleterious and the beneficial roles of B cells and immunoglobulins in MS lesions. We provide alternative hypotheses to explain both damaging and protective antibody responses

Harnessing Radiation Biology to Augment Immunotherapy for Glioblastoma

Glioblastoma is the most common adult primary brain tumor and carries a dismal prognosis. Radiation is a standard first-line therapy, typically deployed following maximal safe surgical debulking, when possible, in combination with cytotoxic chemotherapy. For other systemic cancers, standard of care is being transformed by immunotherapies, including checkpoint-blocking antibodies targeting CTLA-4 and PD-1/PD-L1, with potential for long-term remission. Ongoing studies are evaluating the role of immunotherapies for GBM. Despite dramatic responses in some cases, randomized trials to date have not met primary outcomes. Challenges have been attributed in part to the immunologically “cold” nature of glioblastoma relative to other malignancies successfully treated with immunotherapy. Radiation may serve as a mechanism to improve tumor immunogenicity. In this review, we critically evaluate current evidence regarding radiation as a synergistic facilitator of immunotherapies through modulation of both the innate and adaptive immune milieu. Although current preclinical data encourage efforts to harness synergistic biology between radiation and immunotherapy, several practical and scientific challenges remain. Moreover, insights from radiation biology may unveil additional novel opportunities to help mobilize immunity against GBM

Lipid-specific IgMs induce antiviral responses in the CNS: implications for progressive multifocal leukoencephalopathy in multiple sclerosis

Progressive multi-focal leukoencephalopathy (PML) is a potentially fatal encephalitis caused by JC polyomavirus (JCV). PML principally affects people with a compromised immune system, such as patients with multiple sclerosis (MS) receiving treatment with natalizumab. However, intrathecal synthesis of lipid-reactive IgM in MS patients is associated with a markedly lower incidence of natalizumab-associated PML compared to those without this antibody repertoire. Here we demonstrate that a subset of lipid-reactive human and murine IgMs induce a functional anti-viral response that inhibits replication of encephalitic Alpha and Orthobunyaviruses in multi-cellular central nervous system cultures. These lipid-specific IgMs trigger microglia to produce IFN-β in a cGAS-STING-dependent manner, which induces an IFN-α/β-receptor 1-dependent antiviral response in glia and neurons. These data identify lipid-reactive IgM as a mediator of anti-viral activity in the nervous system and provide a rational explanation why intrathecal synthesis of lipid-reactive IgM correlates with a reduced incidence of iatrogenic PML in MS

The effect of age on cognitive performance of frontal patients

Age is known to affect prefrontal brain structure and executive functioning in healthy older adults, patients with neurodegenerative conditions and TBI. Yet, no studies appear to have systematically investigated the effect of age on cognitive performance in patients with focal lesions. We investigated the effect of age on the cognitive performance of a large sample of tumour and stroke patients with focal unilateral, frontal (n=68), or non-frontal lesions (n=45) and healthy controls (n=52). We retrospectively reviewed their cross sectional cognitive and imaging data. In our frontal patients, age significantly predicted the magnitude of their impairment on two executive tests (Raven's Advanced Progressive Matrices, RAPM and the Stroop test) but not on nominal (Graded Naming Test, GNT) or perceptual (Incomplete Letters) task. In our non-frontal patients, age did not predict the magnitude of their impairment on the RAPM and GNT. Furthermore, the exacerbated executive impairment observed in our frontal patients manifested itself from middle age. We found that only age consistently predicted the exacerbated executive impairment. Lesions to specific frontal areas, or an increase in global brain atrophy or white matter abnormalities were not associated with this impairment. Our results are in line with the notion that the frontal cortex plays a critical role in aging to counteract cognitive and neuronal decline. We suggest that the combined effect of aging and frontal lesions impairs the frontal cortical systems by causing its computational power to fall below the threshold needed to complete executive tasks successfully