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

Branislav Nastasijevic,John Smestad,Arthur E Warrington,Brent R Wright,L James Maher,Moses Rodriguez,Hitoshi Okazawa

doi:10.1371/journal.pone.0039595

Abstract

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.

Highlights

Multiple sclerosis (MS) is a debilitating neurological disease with a prevalence of about 0.1% in the Western world [1]
MS is fundamentally an inflammatory disease leading to central nervous system (CNS) lesions characterized by the loss of myelin required for electrical insulation of neuronal axons [3,4]
We analyzed the specificity of anti-myelin DNA aptamer 3064 and controls 3060 and 3202 by assessing the binding of fluorescent aptamers to crude myelin protein suspension using centrifugal sedimentation to recover bound aptamers (Fig. 2A)

Summary

Introduction

MS is a debilitating neurological disease with a prevalence of about 0.1% in the Western world [1]. Passive transfer of antisera induced by immunization of mice with myelin was observed to promote remyelination in MS-like lesions induced by chronic infection by Theiler’s encephalomyelitis virus (TMEV), suggesting a therapeutic role for anti-myelin antibodies. In the present study we applied in vitro selection to identify a small single-stranded DNA aptamer with affinity for myelin and the ability to promote remyelination in mice (Fig. S1).

Results

Conclusion